WO2018193084A1 - Intracellular kinase associated with resistance against anti-tumour immune responses, and uses thereof - Google Patents
Intracellular kinase associated with resistance against anti-tumour immune responses, and uses thereof Download PDFInfo
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- WO2018193084A1 WO2018193084A1 PCT/EP2018/060172 EP2018060172W WO2018193084A1 WO 2018193084 A1 WO2018193084 A1 WO 2018193084A1 EP 2018060172 W EP2018060172 W EP 2018060172W WO 2018193084 A1 WO2018193084 A1 WO 2018193084A1
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- sik3
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Definitions
- the invention is based on the surprising finding that SIK3 is associated with resistance against anti-tumour immune responses.
- the invention provides methods for treating proliferative diseases using inhibitors of SIK3, especially nucleic acid or small molecule inhibitors of SIK3.
- SIK3 inhibitors to enhance or overcome certain side effects associated with treatments that utilise such signalling pathways
- diagnostic, prognostic and monitoring methods and kits based on the detection of SIK3 in a sample obtained from a subject and screening methods useful for identifying or characterising inhibitors of SIK3.
- approaches by which therapies may lead to the elimination of tumour cells including those that involve or exploit one or more components of the immune system, either directly or indirectly.
- cancerous cells often exploit immune-checkpoints to evade a patient's immune system, such by preventing immune-recognition or down- regulating a tumour-specific cytotoxic T cell (CTL) response, thereby generating resistance against an immune response (Rabinovich et al 2007, Annu Rev Immunol 25:267; Zitvogel et al 2006, Nat Rev Immunol 6:715).
- CTL cytotoxic T cell
- SIKs Salt-inducible kinases
- STK serine tyrosine kinase
- AMPK adenosine monophosphate-activated kinase family.
- SIK1, -2, and -3 Three members (SIK1, -2, and -3) have been identified so far. Amino acid homology of SIK1 with SIK2 and SIK3 is 78% and 68%, respectively, in the kinase domain.
- SIK1 also known as SIK and SNF1LK
- SIK2 also known as QIK, KIAA0781 and SNF1LK2
- SIK3 also known as QSK, KIAA0999 or L19
- the three SIKs have a similar structure ( Figure 1), with an N-terminal kinase domain (catalytic domain), a middle ubiquitin-associated domain (believed important for phosphorylation by LKB1) and a long C-terminal sequence (believed to be a site for further phosphorylation by PKA).
- Figure 1 there are very diverse roles implicated for the various SIKs.
- various SIKs have been implicated in biological processes as diverse as osteocyte response to parathyroid hormone (Wein et al 2016, Nature Commun 7: 13176) to induction of SIK1 by gastrin and inhibition of migration of gastric adenocarcinoma cells (Selvik et al 2014, PLoS ONE 9:ell2485).
- SIK2 and SIK3 have been implicated in diverse biological processes.
- SIK2 these include (as well as immune suppression as described in more detail below) gluconeogenesis, neuronal survival, melanogenesis, hepatic steatosis, and centrosome splitting, as well as SIK2 being implicated in the progression of cancer, certain ovarian cancers depending on the SIK2 kinase for maintenance of cell proliferation and chemo- resistance, and very recently SIK2 as a centrosome kinase required for mitotic spindle formation and a potential target for ovarian and breast cancer therapy in particular for its role in regulation of sensitisation of ovarian cancer to paclitaxel, including the use of SIK2 inhibitors such as ARN-3236 and its analogues (eg ARN-3261) (Zhou et al 2016, doi: 10.1158/1078-0432.CCR-16-1562, and discussion/references therein; WO2014/093383; M
- SIK3 these include (as well as immune suppression as described in more detail below) glucose and lipid homeostasis in mice (Uebi et al 2012, PloS ONE 7:e37803), chondrocyte hypertrophy during skeletal development in mice (Sasagawa et al 2012, Development 139: 1153), osteoarthritis in mice (Yahara et al 2016, Nature Commun 7:10959), SIK3 deficiency exacerbating lipopolysaccharide (LPS)-induced endotoxin shock accompanied by increased levels of pro-inflammatory molecules in mice (Sanosaka et al 2015, Immunology 145:268), SIK3 as a tumour antigen associated with tumourigenesis of ovarian cancer (Chareonfuprasert et al 2011, Oncogene 20:3570) and as a novel mitotic regulator and a target for enhancing antimitotic therapeutic-mediated cell death (Chen et al 2014, Cell Death and Disease 5:
- SIK3 was also reported to possess unique properties, such as the ability to promote class Ila HDAC export independent of its kinase activity and to stimulate cytoplasmic localisation of constitutively nuclear mutants of HDAC4 and HDAC7, highlighting the difference among the SIK family members.
- Walkinshaw reported that PKA counteracts LKB1, SIK2, and SIK3 to inhibit the nuclear export of class Ila HDACs.
- SIK family members have been identified as a key molecular switch whose inhibition reprograms macrophages to an anti-inflammatory phenotype, with macrophages then showing corresponding changes in cytokine expression (increased expression of interleukin-10 (IL-10), and decrease in expression of tumour necrosis factor alpha (TNF-alpha) upon treatment with the pan-SIK small molecule inhibitors MRT67307, MRT199665, KIN 112 and HG-9-91-01 (Clark et al 2012, PNAS 109:16986).
- IL-10 interleukin-10
- TNF-alpha tumour necrosis factor alpha
- Clark reported that HG-9-91-01 appeared to be the most potent SIK family member inhibitor and the most specific for SIK family members, but still showing meaningful inhibition for all three members with most potency against SIK1 and least potency to SIK3, and that these inhibitors elevate IL-10 production by inducing the dephosphorylation of cAMP response element-binding protein (CREB)- regulated transactional coactivator (CRTC) 3.
- CREB cAMP response element-binding protein
- CRTC transactional coactivator
- Dasatinib (SPRYCEL), a small molecule inhibitor of Abl and Src family protein tyrosine kinases (in particular of BCR-ABL), is approved for the treatment of Philadelphia chromosome positive (Ph+) chronic myeloid leukaemia (CML) and Ph+ acute lymphoblastic leukaemia (ALL).
- Dasatinib has been or is under investigation for numerous other cancer types, including solid tumours such as breast cancer, melanoma, ovarian cancer and non-small cell lung cancer, and in particular is under clinical testing in combination with the anti-PD-1 monoclonal antibody nivolumab (OPDIVO) for treating relapsed or refractory Ph+ ALL.
- PPDIVO anti-PD-1 monoclonal antibody nivolumab
- dasatinib with immune suppression, including leading to increased infections and formation of skin cancer in dasatinib-treated CML patients (Sillaber et al 2009, Br J Haematol 144:195); with experimental evidence to support such inhibition of immune responses by dasatinib.
- (i) Schade et al 2007 (Immunobiology 111:1366) reported that dasatinib inhibits T cell activation and proliferation in peripheral blood T lymphocytes (PBTs) in vitro, as well as using an in vivo mouse model.
- PBTs peripheral blood T lymphocytes
- SIK inhibitors could be developed to have increased selectivity towards individual SIKs; such as YKL-05-099 in particular which showed increased selectivity to SIK2. They were able to recapitulate in vivo their previously observed anti-inflammatory phenotypes (including, decreased production of TNF-alpha), and showed that YKL-05-099 treatment led to a dose dependent decrease in phosphorylation of HDAC5 at SIK-regulated Ser25 in total splenic leukocytes.
- Tumour necrosis factor (TNF) - previously known as tumour necrosis factor alpha (TNF-alpha) - was first identified in 1975 (and cloned in 1984) for its ability to induce rapid haemorrhagic necrosis of experimental cancers, although its history could be traced back to the work of Coley in the 1890s.
- TNF tumour necrosis factor
- TNF tumor necrosis factor
- BEROMUN tasonermin
- anti-TNF therapeutics including antibodies that bind to (and sequester) TNF or fragments of recombinant TNF receptors that likewise bind to (and sequester) TNF, thereby reducing the level of free/active TNF.
- anti-TNF agents include: the chimeric mouse Fv and human Fc anti-TNF monoclonal Ig infliximab (IFX), the humanised or fully human Fv) anti- TNF monoclonal Igs adalimumab (ADA), golimumab (GOL) and humicade (HUM); the TNFR2-based human Ig Fc etanercept (ETA) and the pegylated recombinant extracellular TNFR1 onercept (ONE) and pegylated human IgGl Fab' certolizumab pegol (CET).
- IFX chimeric mouse Fv and human Fc anti-TNF monoclonal Ig infliximab
- ADA humanised or fully human Fv anti- TNF monoclonal Igs adalimumab
- ADA golimumab
- HUM humicade
- TNFR2-based human Ig Fc etanercept ETA
- lymphomas Hodgkin's lymphomas, B-cell lymphoma of unknown subtype, peripheral T-cell lymphoma, unspecified lymphomas, and hepatosplenic T cell or gamma-delta T cell lymphoma
- acute leukemias see references in Sedger & McDermott 2014.
- the present invention seeks to provide, in particular, novel therapeutic approaches and methods involving existing or novel compounds; for example compounds that sensitise such cells towards a cytotoxic response of the immune system or components thereof. Furthermore, the invention seeks to provide novel strategies to diagnose, prognose and/or monitor cell resistance to such an immune response or components, as wells as screening approaches for the identification of compounds that are useful in the treatment of proliferative disorders.
- the invention relates to a method for the treatment of a proliferative disorder in a subject by inhibiting SIK3; and/or sensitising cells involved with the proliferative disorder to a cell-mediated immune response, the method comprising administering a SIK3 inhibitor to the subject.
- the invention in a second aspect, relates to a method for the sensitisation of cells involved with a proliferative disorder to a cell-mediated immune response, the method comprising exposing the cells involved with the proliferative disorder to a SIK3 inhibitor.
- the invention relates to a method for the killing of cells involved with a proliferative disorder, the method comprising exposing cells involved with the proliferative disorder to: (i) TNF, a TNF variant and/or an agonist of TNFR1- or TNFR2- signalling; and (ii) a SIK3 inhibitor.
- the invention relates to a method for the treatment of a proliferative disorder in a subject, the method comprising exposing cells involved with the proliferative disorder to: (i) TNF, a TNF variant and/or an agonists of TNFR2- or TNFRl-signalling; and (ii) a SIK3 inhibitor.
- the invention relates to a method for the increase of the therapeutic index of treatment with TNF in a subject being treated therewith for a proliferative disorder, the method comprising administering an inhibitor of SIK3 to the subject.
- the invention relates to a method for the sensitisation of a subject suffering from a proliferative disorder to a therapy involving the administration of TNF to the subject, the method comprising administering an inhibitor of SIK3 to the subject.
- the invention relates to a method for the reduction in risk of a haematological proliferative disorder in a subject being treated with an anti-TNF agent, the method comprising administering an inhibitor of SIK3 to the subject.
- the invention also relates to various determination methods, and to items and kits useful for such determination methods, as well as to various methods for identifying compounds [25]
- the figures show:
- Figure 1 Pictorial representation of the comparative structural features of SIK1, SIK2 and SIK3. N-terminal kinase domains represented by grey rectangles, middle ubiquitin-associated domains represented by white rectangles and C-terminal sequence represented by light grey bar.
- FIG. 2 Luciferase-based cytotoxicity assay for the assessment of T cell-mediated killing of siRNA transfected PANC-l-luc cells.
- Graph shows remaining luciferase activity (RLU) of tumour cells after 20h challenge with TIL#1 or survivin-specific T cell clones, normalised to the signal of the scrambled control siRNA (siCtrl).
- FIG. 1 PANC-l-luc cells were transfected either with single (si, s2, or s3) or pooled (pool) siRNA sequences targeting SIK3. Scrambled siRNA was used as control (siCtrl). After 72h, mRNA expression was evaluated using qPCR. Data are normalised to GAPDH.
- Figure 4 (A) Chromium release assay for the detection of T-cell mediated cytotoxicity of PANC-1 cells after 6h co-culture with TIL#2 after transfection with the indicated siRNA. (B) Western blot analysis for the detection of PD-L1 and CEACAM6 protein levels in PANC-1 cells 72h from the indicated siRNA transfection. Scrambled siRNA was used as negative control.
- FIG. 5 Real-time live cell microscopy for the evaluation of tumour cell death using YOYO-1 dye. 72h from transfection with the indicated siRNAs, MCF-7 (A) and SW480 (B) were co-cultured either with survivin-specific T cell clones or with TIL#1, respectively. Graph shows the area of YOYO-1+ cells/well ( m2/well) as a measure of cell death.
- FIG. 6 M579-luciferase expressing melanoma cells (M579-A2-luc) were transfected with the indicated siRNAs, with luciferase-based killing assay performed 20h after co-culture. (B) M579-A2-luc cells were transfected with SIK3 overexpression vector (SIK3 over) or control vector (EV), with T cell mediated cytotoxicity was assessed as in (A).
- SIK3 over SIK3 overexpression vector
- EV control vector
- FIG. 7 (A) PANC-1 cells were co-culture with TIL#1 in the presence of increasing concentrations of the SIK inhibitor HG-9-91-01, and T cell mediated cytotoxicity was measured using the luciferase-based killing assay as in Figure 3C. The signal between cytotoxicity to viability settings is represented as a ratio. (B) Shows the absolute signal for the two settings shown as a ratio in (A). (C) Luciferase-based cytotoxicity assay. PANC-l-luc cells were transfected with the indicated siRNAs for 72h and then incubated with the stated concentration of dasatinib before stimulation with 100 ng/mL of rHuTNF for 18h (or no stimulation).
- E Influenza
- Flu antigen-specific T cell-mediated cytotoxicity of PANCl-luc tumour cells after siRNA knock-down of each of the three SIK family members compared to siRNA knock-down of PD-L1 (and scrambled siRNA control).
- G Effect of dasatinib on TNF- mediated cytotoxicity of M579-A2-luc tumour cells after siRNA knock-down of SIK1 and SIK2 compared to scrambled siRNA control.
- FIG. 8 PANC-l-luc cells were transfected either with single (si, s2, or s3) or pooled (pool) siRNA sequences targeting SIK3. Scrambled siRNA was used as control (siCtrl). After 72h, tumour cells were treated with the supernatant (Sup) of tumour-activated (A), unstimulated (B), or CD3-CD28 bead-activated T cells (C). After 20h, the effect of the supernatant on tumour cell cytotoxicity was measured using luciferase-based killing assay. For each experiment, siRNA transfected tumour cells were treated with culture medium (Unst) as negative control, and no significant changes were observed.
- Graphs show the remaining luciferase activity (RLU) after stimulation with indicated supernatants represented as fold change luciferase activity compared to unstimulated siCtrl treatment.
- RLU luciferase activity
- FIG. 9 (A) Supernatant from CD3-CD28 bead-stimulated T cells was incubated with 100 (+), 300 (++) or 900 (+++) ng/mL of anti-TNF neutralising antibody. Isotype control (Ctrl Ab) was used at concentration of 900 ng/mL. Afterwards, siSIK3 transfected PANC-l-luc cells were subjected to the pre-treated supernatant for 24h and cytotoxicity was measured using luciferase-based killing assay. Graph shows normalised values of remaining luciferase activity (RLU) of tumour cells. (B) Luminex assay for detection of secreted TNF from TIL#1.
- TIL#1 was co- cultured either with PANC-1 cells or with CD3/CD28 beads (polyclonal stimulation). 24h after stimulation, supernatant was collected for TNF measurement.
- C Incubation of supernatant from CD3-CD28 bead-stimulated T cells with anti- TRAIL and anti-FASL neutralising antibodies (as per (A)) did not lead to a reduction in cytotoxicity after SIK3 incubation, unlike incubation with the anti-TNF neutralising antibody.
- Figure 10 (A) Dose-response effect of rHuTNF treatment on the viability of the indicated siRNA transfected PANC-l-luc cells. Cytotoxicity was measured as in ( Figure 9A). Graph shows the raw luciferase activity (RLU) of tumour cells after treatment with rHuTNF. (B) Effect of lOOng/mL TNF treatment on the viability of PANC-1 cells after transfection with the indicated siRNA. Cell death was evaluated using real-time live cell microscopy, measuring the nuclear incorporation of YOYO-1 dye. Graph shows the area of YOYO-1+ cells/well ( m2/well) of images after 6h stimulation, with cumulative data of 9 different pictures from the same experiment.
- FIG 11 (A) FACS analysis of PANC-1 cells incubated with anti-TNFRl antibody (Hyculture GmbH, Cat No: HM2020B) detected with R-Phycoerythrin AffiniPure F(ab')2 Fragment Goat Anti-Mouse IgG (H+L) (Jackson Immuno Research, Cat No: 115-116-146 46), showing significant expression of TNFR1 by PANC-1 cells.
- FACS analysis of cells incubated with anti-TNFR2 antibody (Acris Antibodies GmbH, Cat No: AM20008AF-N) detected as for the anti-TNFRl antibody, shows significant expression of TNFR2 by TILS (B), but not by PANC-1 cells (C).
- FIG. 12 SIK3 or scrambled control (siCtrl) siRNA transfected PANC-l-luc cells were treated with 100 ng/mL of rHuTNF. After the indicated time points, tumour cells were harvested and total protein fraction was isolated. Luminex assays were performed for active caspase 8 (A), active caspase 9 (B) and pJNK (C). Graphs show median fluorescent intensity (MFI) of analyte-specific beads after normalisation to GAPDH.
- A active caspase 8
- B active caspase 9
- C pJNK
- FIG. 13 (A) Luciferase-based cytotoxicity assay. PANC-l-luc cells were transfected with the indicated siRNAs for 72h and stimulated with 100 ng/mL of rHuTNF for 24h. Graph shows the remaining luciferase activity of tumour cells.
- C PANC-1 cells were transiently transfected either with SIK3 overexpressing vector (SIK3 over) or with control vector (EV) for 48h. p65 NF-KB ELISA was conducted as in (B).
- Figure 14 Two-dimensional hierarchical clustering (Z-score transformed, normalised counts per million; Manhattan distance, Ward method) of 386 genes that were significantly regulated by TNF after 4h and significantly affected by SIK3 knock-down by siRNA.
- PANC1 cells depleted of SIK3 by treatment with SIK3 siRNA (siSIK3) and control cells treated with scrambled control siRNA (siCtrll) in each with and without exposure to TNF (each condition duplicated).
- Figure 15 Real-time live cell microscopy showing mean +/- SEM of TIL209-mediated lysis of M579 cells transduced with shCtrl or shSIK3 lentiviral constructs. The graph indicates the area of YOYO-1+ cells/well (um2/well).
- FIG. 17 Relative tumour cell survival (Normalised RLU by cytotoxicity/via bility) of certain compounds of general formula 1 in the assay using M579-Al-luc described in Example 9 at various concentrations either alone (squares) or in combination with lOng/mL of TNF (circles). Also shown are indicative inhibitory activities of the compound for SIK-family members and for the related kinases ABLl and SRC, shown with the indicators used for Table 4.
- A The pan-SIK and ABLl & SRC inhibitor, compound Bl;
- B The ABLl & SRC inhibitor, compound B8.
- C The SIK1, SIK2 and ABLl & SRC inhibitor, compound B4.
- FIG. 18 M579 A2 tumour cell survival (RLU) in the luc assay for SIK-family member selective inhibitors in combination with lOng/mL.
- RLU tumour cell survival
- the invention relates to a method for the treatment of a proliferative disorder in a subject by inhibiting SIK3, the method comprising administering a SIK3 inhibitor to the subject.
- the invention relates to a method for the treatment of a proliferative disorder in a subject by sensitising cells involved with the proliferative disorder to a cell-mediated immune response, the method comprising administering a SIK3 inhibitor to the subject.
- the invention relates to a method for the treatment of a proliferative disorder in a subject, by inhibiting SIK3 and (for example, thereby) sensitising cells involved with the proliferative disorder to a cell-mediated immune response, the method comprising administering a SIK3 inhibitor to the subject.
- the invention relates to an inhibitor of SIK3 for use in the treatment of a proliferative disorder in a subject, wherein the treatment involves (eg is mediated by): (i) sensitising cells involved with the proliferative disorder to a cell-mediated immune response; and/or (ii) inhibiting SIK3.
- the invention pertains to a use of a SIK3 inhibitor for the manufacture of a medicament for the treatment of a proliferative disease in a subject, wherein the treatment involves (eg is mediated by): (i) sensitising cells involved with the proliferative disorder to a cell-mediated immune response; and/or (ii) inhibiting SIK3.
- the manufacture of the medicament includes a step of preparing, formulating, or otherwise providing, the SIK3 inhibitor in a form suitable for specific delivery of the SIK3 inhibitor to cells involved with the proliferative disorder.
- the inhibitor in such treatment: (i) sensitises the cells involved with the proliferative disorder to the cell-mediated immune response; and/or (i) inhibits SIK3.
- the SIK3 inhibitor is one capable of: (i) sensitising cells involved with the proliferative disorder to a cell-mediated immune response; and/or (ii) inhibiting SIK3.
- the invention relates to a method for the sensitisation of cells involved with a proliferative disorder to a cell- mediated immune response in the treatment of the proliferative disorder in a subject, the method comprising administering a SIK3 inhibitor to the subject; and in another further aspect, and as may be further described, defined, claimed or otherwise disclosed herein, the invention relates to a method for the inhibition of SIK3 in the treatment of a proliferative disorder in a subject, the method comprising administering an SIK3 inhibitor to the subject.
- the invention relates to an inhibitor of SIK3 (eg, a SIK3 inhibitor) for use as a medicament for: (i) sensitising cells involved with a proliferative disorder to a cell-mediated immune response; and/or (ii) inhibiting SIK3.
- a SIK3 inhibitor for use as a medicament for: (i) sensitising cells involved with a proliferative disorder to a cell-mediated immune response; and/or (ii) inhibiting SIK3.
- the invention relates to a SIK3 inhibitor for use as a medicament (eg an immuno-oncology medicament) sensitising cells involved with a proliferative disorder (such as a tumour or cancer) to a cell-mediated immune response, for example sensitising cells involved with a proliferative disorder to killing (cell-death) that may be induced by the cell-mediated immune response.
- a medicament eg an immuno-oncology medicament
- a proliferative disorder such as a tumour or cancer
- a cell-mediated immune response for example sensitising cells involved with a proliferative disorder to killing (cell-death) that may be induced by the cell-mediated immune response.
- an "immune-oncology" medicament is one that would be recognised by the person of ordinary skill, and includes a medicament that is indended to (eg, specifically designed to) enhance one or more components of the immune system of an organism (such as a human) towards cancerous or tumourous cells present in such organism.
- An immune-oncology medicament may be one (eg an antibody) than binds to an extrinsic immune (inhibitory) checkpoint molecule (such as one described elsewhere herein) and that (eg directly) suppresses T cell function against the cancerous or tumourous cells, or an immune-oncology medicament may be one that inhibits an immune regulator (such as SIK3, as in the present invention) that is intrinsic to the cancerous or tumourous cells where such intrinsic immune regulator does not actively (eg directly) suppress T cells but rather protects the tumour or cancer cells from an immune response via a resistance mechanism.
- an immune regulator such as SIK3, as in the present invention
- the cells involved with a proliferative disorder may be sensitised to killing (cell-death) by (such as induced by) the cell-mediated immune response.
- SIK3 Salt-inducible kinase 3
- SIK3 is a member of a subfamily of serine/threonine protein kinases including SIK1, SIK2, and SIK3 that belong to an AMP-activated protein kinase (AMPK) family.
- AMPK AMP-activated protein kinase
- Pertinent information on the human SIK3 protein is accessible on UniProt: Q9Y2K2 (Entry version 138 of 15-Mar-2017) and a SIK3 protein in context of the invention has, preferably, the domain structure shown in Figure 1, and more preferably comprises an amino acid sequence shown in any of SEQ ID NOs: 1 to 4 (SIK3, Entry version 138 of 15-Mar-2017) or in any of SEQ ID NOs 13 to 16 (SIK3, Entry version 144 of 28-Mar-2018), in particular of SEQ ID NOs: 1 or 13.
- SIK3 is a cytoplasmatic protein with serine/threonine kinase activity which is regulated through phosphorylation of a conserved threonine residue (position 163) in the T-loop of the kinase domain by the LKB1 complex; a phosphorylation which is reported as essential for catalytic activity of SIK3 (Lizcano, J. M. et al.; EMBO J. 23, 833-843 (2004)).
- phosphorylated SIK3 shall denote a SIK3 protein that is phosphorylated substantially as SIK3 protein can be (eg is) phosphorylated by LKB1, wherein preferably such phosphorylated SIK3 comprising a phosphor-threonine at amino acid position 163.
- a phosphorylated SIK3 in context of the invention is an SIK3 protein that is activated in its cell-biological context. At least four protein isoforms (SIK3- 001 to SIK3-004) generated by alternative splicing of the SIK3 gene product are known.
- the human SIK3 gene is located at chromosomal position llq23.3 (HGNC gene Symbol Acc: HGNC:29165), and is conserved in many species such as in chimpanzee, Rhesus monkey, dog, cow, mouse, rat, chicken, zebrafish, and frog.
- SIK3 in some embodiments of the invention may also pertain to variants of the human SIK3 protein having an amino acid sequence that is substantially identical to, or of at least 80%, preferably 85%, more preferably 90, 95, 96, 97, 98, 99, or 100% sequence identity to, the amino acid sequence shown in any of SEQ ID NO: 1 to 4 or in any of SEQ ID NOs 13 to 16, in particular of SEQ ID NOs: 1 or 13, as determined using, e.g., the "Blast 2 sequences" algorithm described by Tatusova & Madden 1999 (FEMS Microbiol Lett 174: 247-250), and which (preferably) retain biological activity identical or substantially identical to the respective reference SIK3 (eg to phosphorylate one or more class II (eg Ila) HDACs, such as HDAC4).
- class II eg Ila
- Preferred variants of SIK3 protein comprise sequence variants thereof due to sequence polymorphism between and within populations of the respective species, as well as mutations compared to the wild-type sequence of SIK3 which are located in or in close proximity to the activity loop or activation loop (T- loop) of SIK3.
- a preferred variant of SIK3 protein is a SIK3 T163 mutation, such as a mutation affecting the activation of SIK3.
- a SIK3 protein of the invention is not a SIK1 (synonyms: SIK and SNF1LK) protein and/or is not a SIK2 (synonyms: QIK, KIAA0781 and SNF1LK2) protein.
- SIK3 can mean, as applicable to the context (if not more specifically indicated), a SIK3 protein (such as one described above) or an mRNA molecule encoding such a SIK3 protein.
- SIK3 inhibitor is any moiety that inhibits SIK3, which can mean inhibition of the expression (eg the amount), function, activity and/or stability of SIK3, especially of mRNA and/or protein of SIK3, and in particular of phosphorylated SIK3.
- a SIK3 inhibitor may impair, suppress, reduce and/or lower the expression of SIK3 (eg SIK3 mRNA or protein) in a cell.
- expression means in this context the cellular process of transcribing a gene into an mRNA and the following translation of the mRNA into a protein (and in certain embodiment, the subsequent transport and localisation of such protein).
- Gene expression therefore may thus refer only to the generation of mRNA, irrespectively from the fate of the so produced mRNA, or alternatively/additionally to the translation of the expressed mRNA into a protein (or transport and localisation of such protein).
- protein expression on the other hand may refer to the complete cellular process of synthesis of proteins and/or transport/localisation thereof into certain cellular compartments.
- a SIK3 inhibitor may impair (eg, induces a decrease or reduction in) the efficiency, effectiveness, amount or rate of one or more activities of SIK3 (for example, by impairing the expression of SIK3 protein and/or amount of phosphorylated SIK3 protein), such as one or more of those activities described herein, for example, the activity of SIK3 to phosphorylate class II (eg Ila) HDACs (eg HDAC4) and/or to sensitise a cell involved with a proliferative disorder to a cell-mediated immune response.
- SIK3 phosphorylate class II
- HDACs eg HDAC4
- SIK3 inhibitor may have a negative effect towards the stability of SIK3 (eg SIK3 mRNA or protein), which shall be understood in its broadest sense, and shall include inhibitors which, for example, interfere with and reduce the SIK3 protein half-life or interfere with and disturb SIK3 protein folding, protein presentation or transport/localisation within the cell.
- SIK3 eg SIK3 mRNA or protein
- Such a SIK3 inhibiting moiety can act directly, for example, by binding to SIK3 and decreasing the amount or rate of one or more of the properties of SIK3 such as its expression, function and/or stability, in particular its ability to act as a kinase (eg to phosphorylate HDAC4), for example by reducing the amount or activity of phosphorylated SIK3 in the cell.
- a kinase eg to phosphorylate HDAC4
- a SIK3 inhibitor may also decrease the amount or rate of SIK3 function or activity by impairing its expression, stability, for example, by binding to SIK3 protein or mRNA and modifying it, such as by removal or addition of a moiety, or altering its three-dimensional conformation; and by binding to SIK3 protein or mRNA and reducing its stability or conformational integrity.
- a SIK3 inhibitor may, alternatively, act indirectly, for example, by binding to a regulatory molecule or gene region to modulate such regulatory protein or gene region function and hence consequentially affect a decrease in the amount or rate of SIK3 expression (eg amount), function/activity and/or stability, in particular by impairing one or more activity of SIK3 protein or mRNA (such as by changing the amount or rate of expression and/or stability of SIK3 protein or mRNA).
- an SIK3 inhibitor can act by any mechanisms that impair, such as result in a decrease in, the amount or rate of SIK3 expression (eg amount), function/activity and/or stability.
- SIK3 inhibitors that act directly on SIK3 include: (i) siRNA or shRNA molecules that bind to and reduce expression of SIK3 mRNA; and (ii) small molecule moieties that bind to the catalytic domain of SIK3 and reduce the kinase activity of SIK3.
- Non-limiting examples of SIK3 inhibitors that act indirectly on SIK3 include: (i) siRNA or shRNA molecules that bind to and reduce expression of LKB1 mRNA; and (ii) small molecule moieties that bind to the catalytic domain of LKB1 and reduce the kinase activity of LKB1, that in each case by reduction in the amount or activity of LKB1 protein, consequential reduce the amount (and hence activity) of phosphorylated SIK3 protein.
- An indirect SIK3 inhibitor may also be, for example, an antagonist (such as a blocking antibody) to the glucagon receptor (or insulin receptor), which then decreases the amount and/or activity of SIK3 (or phospo-SIK3) protein in the cell.
- SIK3 inhibitors are described elsewhere herein, including those as may be characterised by the applicable functional and/or structural features set out herein.
- a "subject” includes all mammals, including without limitation humans, but also non-human primates such as cynomolgus monkeys. It also includes dogs, cats, horses, sheep, goats, cows, rabbits, pigs and rodents (such as mice and rats). It will be appreciated that a particularly preferred subject according to the invention is a human subject, such as a human suffering from (or at risk of suffering from) a disorder, disease or condition, for example a human patient.
- therapy is synonymous with treating a disease, disorder or condition, which includes reducing symptoms of the disease, disorder or condition, inhibiting progression of the disease, disorder or condition, causing regression of the disease, disorder or condition and/or curing the disease, disorder or condition.
- treatment in the present invention is meant to include therapy, e.g. therapeutic treatment, as well as prophylactic or suppressive measures for a disease (or disorder or condition).
- therapy e.g. therapeutic treatment
- successful administration of a SIK3 inhibitor prior to onset of the disease results in treatment of the disease.
- Treatment also encompasses administration of a SIK3 inhibitor after the appearance of the disease in order to ameliorate or eradicate the disease (or symptoms thereof).
- Administration of a SIK3 inhibitor after onset and after clinical symptoms, with possible abatement of clinical symptoms and perhaps amelioration of the disease also comprises treatment of the disease.
- Those "in need of treatment” include subjects (such as a human subject) already having the disease, disorder or condition, as well as those prone to or suspected of having the disease, disorder or condition, including those in which the disease, disorder or condition is to be prevented.
- the disease, disorder or a condition in the context of the herein described invention, is a proliferative disorder (including a condition or symptom associated with such disorder).
- a proliferative disorder refers to a disorder characterised by abnormal proliferation of cells.
- a proliferative disorder does not imply any limitation with respect to the rate of cell growth, but merely indicates loss of normal controls that affect growth and cell division.
- cells of a proliferative disorder can have the same cell division rates as normal cells but do not respond to signals that limit such growth.
- neoplasm or tumour which is an abnormal growth of tissue or cells. Cancer is art understood, and includes any of various malignant neoplasms characterised by the proliferation of cells that have the capability to invade surrounding tissue and/or metastasise to new colonisation sites.
- Proliferative disorders include cancer, atherosclerosis, rheumatoid arthritis, idiopathic pulmonary fibrosis and cirrhosis of the liver.
- Non-cancerous proliferative disorders also include hyperproliferation of cells in the skin such as psoriasis and its varied clinical forms, Reiter's syndrome, pityriasis rubra pilaris, and hyperproliferative variants of disorders of keratinisation (e.g., actinic keratosis, senile keratosis), scleroderma, and the like.
- the proliferative disorder is a cancer or tumour, in particular a solid tumour (including a condition or symptom associated with such cancer or tumour).
- Such proliferative disorders including but not limited to head and neck cancer, squamous cell carcinoma, multiple myeloma, solitary plasmacytoma, renal cell cancer, retinoblastoma, germ cell tumours, hepatoblastoma, hepatocellular carcinoma, melanoma, rhabdoid tumour of the kidney, Ewing Sarcoma, chondrosarcoma, any haemotological malignancy (e.g., chronic lymphoblastic leukemia, chronic myelomonocytic leukemia, acute lymphoblastic leukemia, acute lymphocytic leukemia, acute myelogenous leukemia, acute myeloblasts leukemia, chronic myeloblastic leukemia, Hodgekin's disease, non- Hodgekin's lymphoma, chronic
- the various aspects of the invention relate to, for example the SIK3 inhibitors are used in treatments for proliferative disorders that include those described herein.
- the proliferative disorder can be a tumour, in particular a solid tumour.
- the cell that is sensitised to the cell-mediated immune response is one involved with the proliferative disorder (eg, a cell associated with the proliferative disorder), which in certain embodiments such cell is one involved in the proliferative disorder (eg, a cell that is abnormally proliferating, such as one that is over-proliferating).
- the proliferative disorder eg, a cell that is abnormally proliferating, such as one that is over-proliferating.
- such cell may be a cell characterised by loss of normal controls that affect its growth and cell division, such as a cell of a neoplasm or tumour.
- such cell may be a cancerous cell or one that is derived form or is a cell of a cancer or tumour.
- such cell may be skin cell, such as one showing hyperproliferation such as one involved in psoriasis, Reiter's syndrome, pityriasis rubra pilaris or scleroderma.
- a cell may be "involved with a proliferative disorder” if, for example, it is associated therewith, such as it being a causative factor in such proliferative disorder or if it is affected by such proliferative disorder.
- a cell is "involved with a proliferative disorder” if the cell is characterised by an abnormal proliferation such as abnormal cell growth or cell division, and if the abnormal cell growth or cell division is part of the pathology of, or causative for, the proliferative disease.
- a cell "involved with a proliferative disorder", in those embodiments wherein the proliferative disorder is a tumour or cancer, can as a non-limiting example, be a tumour (or cancer) cell, or a cell of derived from (tissue) of such tumour or cancer; in particular of a solid tumour.
- the SIK3 inhibitor may inhibit SIK3 in the cell involved with the proliferative disorder (eg the tumour cell).
- the SIK3 inhibitor may inhibit SIK3 in such cell preferentially to inhibiting SIK1 and/or SIK2 in such cell; and/or may inhibit SIK3 in such cell preferentially to inhibiting SIK1 and/or SIK2 and/or SIK3 in one or more types of immune cells.
- the SIK3 inhibitor may inhibit SIK3 in the cell involved with the proliferative disorder (eg the tumour cell) preferentially to inhibiting SIK1 and/or SIK2 and/or SIK3 in macrophages and/or dendritic cells (in particular, those capable of or producing IL-10).
- the proliferative disorder eg the tumour cell
- SIK1 and/or SIK2 and/or SIK3 in macrophages and/or dendritic cells (in particular, those capable of or producing IL-10).
- the SIK3 inhibitor may be administered to the subject, in particular in an amount (such as a dose) that is effective to, inhibit SIK3 and/or that is effective to sensitise the cells involved with the proliferative disorder to the cell-mediated immune response. Suitable amounts, formulations and means for such administration are described elsewhere herein.
- the SIK3 inhibitor is administered in an amount (such as a therapeutically effective amount) that is effective to reduce activity of SIK3, preferably of SIK3 in (of) the cells involved with the proliferative disorder.
- a "therapeutically effective amount" of the SIK3 inhibitor can be an amount that is capable to reduce the activity of the SIK3 to an applicable level, but that does not lead to significant (eg intolerable) side effects or over-dosage in respect of other activities of the SIK3 inhibitor.
- such an amount of the SIK3 inhibitor may be one that is not effective to reduce the activity of ABL1 and/or SRC kinase, such as ABL1 and/or SRC kinase in (of) the cells involved with the proliferative disorder.
- ABL and SRC main kinase targets
- dasatinib was to be administered in an amount effective to inhibit SIK3, its main kinase targets (ABL and SRC) would also be inhibited, and possibly to such a degree that an over-dosage of dasatinib, or other side effects such as those mediated by over inhibition of ABL and/or SRC would occur.
- dasatinib may not be able to inhibit SIK3 in-vivo without inhibiting ABL and/or SRC in the same cell, and any ABL or SRC present in such cell may sequester the (majority of) dasatinib in the cell to such an extent that no dasatinib would remain to (effectively) act as a SIK3 inhibitor. Accordingly, in certain embodiments, dasatinib may be considered not to be a SIK3 inhibitor in the context of the present invention, when acting in vivo, such as in cells involved with a proliferative disporder.
- a ASl inhibitor in the context of the present invention may inhibit ASl more potently than dasatinib and/or may inhibit ABL and/or SRC kinases less potently than dasatinib.
- a preferred ASl inhibitor in the context of the present invention may inhibit ASl with a (biochemical) IC50 of less than about ⁇ , 50nM, 25nM or ⁇ (such as less than about 25nM) and inhibits ABL and SRC each with an IC50 of greater than about 25nM, 50nM, ⁇ or 500nM (such as greater than about ⁇ ), in each case where such IC50 may be determined using a method analogous a biochemical kinase assay described in Example 11 or 13).
- the activity of SIK3 is effectively inhibited (reduced), and/or the activity of ABL and/or SRC is not effectively inhibited (reduced); in each case, preferably referring to the SIK3, ABL and/or SRC kinase in (of) the cells involved with a proliferative disorder.
- an "effective" inhibition (or reduction) may include one where the activitiy is lowered by a degree (or to a level) that has a physiological effect (eg to a therapeutically effective level), such as a reduction by about 10%, 20%, 50%, or more than 50% such as 70% or 90% of activity of the respective kinase.
- a degree of a level that has a physiological effect
- a reduction by about 10%, 20%, 50%, or more than 50% such as 70% or 90% of activity of the respective kinase.
- the desired level of reduction may be one that is less than that desired for a reduction in SIK3.
- lymphocytes white blood cells
- B cells and T cells are the major types of lymphocytes and are derived from hematopoietic stem cells in the bone marrow. B cells are involved in the humoral immune response, whereas T cells are involved in cell-mediated immune response.
- the immune cell can be a myeloid cell eg a T cell, and in particular (such as when an increase in cell-mediated immune response is required, such as to treat a cancer) the T cell can be a cytotoxic T cell (also known as TC, cytotoxic T lymphocyte, CTL, T-killer cell, cytolytic T cell, CD8+ T-cell or killer T cell).
- a CTL is a T-cell that is involved in the killing of cancer cells, cells that are infected (particularly with viruses), or cells that are damaged in other ways.
- Other preferred immune cells for such embodiments can include Tumour-Infiltrating Lymphocytes (TILs). TILs are white blood cells that have left the bloodstream and migrated into a tumour.
- TILs are a mix of different types of cells (i.e., T cells, B cells, NK cells, macrophages) in variable proportions, T cells being the most abundant cells. TILs can often be found in the stroma and within the tumour itself, and are implicated in killing tumour cells. The presence of lymphocytes in tumours is often associated with better clinical outcomes.
- cell-mediated immune response may include, but is not limited to, a response in a host organism involving, utilising, and/or promoting any one or combinations of T cell maturation, proliferation, activation, migration, infiltration and/or differentiation, and/or the activation/modulation/migration/infiltration of a macrophage, a natural killer cell, a T lymphocyte (or T cell), a helper T lymphocyte, a memory T lymphocyte, a suppressor T lymphocyte, a regulator T lymphocyte, and/or a cytotoxic T lymphocyte (CTL), and/or the production, release, and/or effect of one or more cell-secretable or cell-secreted factor such as a cytokine or autocoid (in particular a pro-inflammatory cytokine such as TNF), and/or one or more components of any of such processes (such as a cytokine or autocoid, particular a pro-inflammatory cytokine such as TNF).
- a cytokine or autocoid in particular
- cell-mediated immune response may include a cellular response involving a genetically engineered, in-vitro cultured, autologous, heterologous, modified, and/or transferred T lymphocyte, or it may include a cell-secretable or cell- secreted factor (such as a cytokine or autocoid, in particular a pro-inflammatory cytokine such as TNF) produced by genetic engineering.
- a cell-mediated immune response is preferably not a humoral immune response, such as an immune response involving the release of antibodies.
- the cell-mediated immune response is an anti-tumour cell-mediated immune response.
- a cytotoxic cell-mediated immune response such as a cytotoxic T cell and/or TNF exposure
- the cell mediating the cell-mediated immune response may be mediated by a cell, such as an immune cell, capable of secreting (eg secreting) pro-inflammatory cytokine, such as one selected from the group consisting of: interleukin-1 (IL-1), IL-12, and IL-18, tumour necrosis factor (TNF), interferon gamma (IFN- gamma), and granulocyte-macrophage colony stimulating factor.
- the proinflammatory cytokine is tumour necrosis factor (TNF) [alpha].
- the cell-mediated immune response may a cell-secretable or cell-secreted factor (such as a cytokine or autocoid), in particular one secretable or secreted by an immune cell.
- the cell-mediated immune response is a pro-inflammatory cytokine, in particular tumour necrosis factor (TNF).
- TNF tumour necrosis factor
- cells that are so sensitised may, when in the presence of (eg exposed to) a cell-mediated immune response, be killed more easily (such as more rapidly, a greater proportion of cells dying or being killed and/or upon a lower amount or exposure of the cell- mediated immune response) than analogous cells that have not been so "sensitised".
- cell(s) so sensitised may be induced into cell-death (eg apoptosis) upon exposure to a lower number of T cells or to a lower concentration of TNF (such as about 10%, 20%, 30% 40%, 50% or more than 50% fewer T cells or lower concentration of TNF).
- cells involved with the proliferative disorder may be sensitised to cell-death/killing (eg by entry into apoptosis) by a cell-mediated immune response (such as CTL or a proinflammatory cytokine eg TNF).
- a cell-mediated immune response such as CTL or a proinflammatory cytokine eg TNF.
- TNF encompasses endogenous TNF of any organism where such is present, and preferably of animals or mammals, such as humans.
- human TNF may encompass endogenous proteins as disclosed in inter alia Pennica et al. 1984 (Nature 312: 724-9) and in the UniProtKB/Swiss-Prot database with the entry No P01375 (for example, entry version 224 of 15-Mar-2017), as well as any sequence variants thereof due to normal sequence polymorphism between and within human populations.
- the term may encompass endogenous TNF proteins as annotated in the UniProtKB/Swiss-Prot database for bovine (Q06599), dog (P51742), goat (P13296), guinea pig (P51435), cat (P19101), horse (P29553), mouse (P06804), chimp (Q8HZD9), pig (P23563), rabbit (P04924), rat (P16599) and others, as well as any sequence variants thereof due to sequence polymorphism between and within populations of each respective species.
- TNF particularly encompasses the soluble, secreted cytokine form of TNF, including monomeric as well as, preferably, the typically more active trimeric forms thereof (see, e.g., Smith & Baglioni 1987. J Biol Chem 262: 6951-4).
- the primary amino acid sequences of soluble forms of endogenous TNF are indicated in the above mentioned UniProtKB/Swiss-Prot database entries for the respective exemplified organisms.
- TNF may also encompass membrane-bound forms of TNF expressed on the surface of some cell types (see, e.g., Kriegler et al. 1988. Cell 53: 45-53).
- TNF may also encompass synthetic or recombinant proteins whose primary amino acid sequence is identical or substantially identical ("substantially identical", as used throughout this specification, generally refers to ⁇ 80%, e.g., ⁇ 85%, preferably ⁇ 90%, more preferably ⁇ 95%, even more preferably ⁇ 98% or ⁇ 99% sequence identity) to the sequence of an endogenous TNF, as determined using, e.g., the "Blast 2 sequences" algorithm described by Tatusova & Madden 1999 (FEMS Microbiol Lett 174: 247-250), and which (preferably) retain biological activity identical or substantially identical to the respective endogenous TNF, as determined using, e.g., the cytotoxicity tests described by Flick & Gifford 1984 (J Immunol Methods 68: 167-75).
- substantially identical generally refers to ⁇ 80%, e.g., ⁇ 85%, preferably ⁇ 90%, more preferably ⁇ 95%, even more preferably ⁇ 98% or ⁇ 99% sequence identity
- TNF may, in particular, refer herein to endogenous TNF, soluble and/or membrane bound, preferably soluble, produced by cells, tissues, organs or organisms, preferably human.
- TNF exogenous forms of tumour necrosis factor, in particular those produced by recombinant technologies and, in certain embodiments, may be administered to subjects, or exposed to or contacted with cells in various aspects and embodiments of the invention.
- the TNF may be a recombinant TNF uses as a therapeutic, such as tasonermin (BEROMUN).
- the cell-mediated immune response can be mediated by a pro-inflammatory cytokine-secreting cell, such as a lymphocyte (eg a T cell), in particular a cytotoxic T lymphocyte (CTL).
- a pro-inflammatory cytokine-secreting cell such as a lymphocyte (eg a T cell), in particular a cytotoxic T lymphocyte (CTL).
- a lymphocyte eg a T cell
- CTL cytotoxic T lymphocyte
- the cell-mediated immune response may induce killing (eg cell-death, such via apoptosis) of cells involved with the proliferative disorder.
- the treatment (method) may comprise (eg may involve) that (or be mediated by) the cell-mediated immune response induces such killing of cells involved with the proliferative disorder.
- the cells involved with the proliferative disorder may be killed (eg induced into cell death) by one or more cytotoxic processes, in particular those that are endogenous to such cell such as programmed cell death (PCD).
- cytotoxic processes may include, but are not limited to, necrosis (in particular necroptosis), apoptosis, anoikis, autophagy, ferroptosis, mitotic catastrophe and activation-induced cell death.
- the cells involved with the proliferative disorder eg the tumour cells
- the SIK3 inhibitor is administered to not kill such cells in the absence of the cell-mediated immune response (eg in the absence of TNF).
- the SIK3 inhibitor may be administered in an amount (eg in a dose) that is not effective to kill such cells in the absence of the cell-mediated immune response.
- the cell-mediated immune response may involve at least one immune cell effector molecule, in particular an effector molecule that is secretable or secreted by an immune cell.
- the effector molecule can be a pro-inflammatory cytokine, preferably tumour necrosis factor (TNF).
- the effector molecule is not a cell effector molecule selected from Fas ligand (FasL or CD95L) and TNF-related apoptosis-inducing ligand (TRAIL, CD253 or TNFSF10).
- the SIK3 inhibitor may be administered to the subject (eg in an amount or dose effective) with the intent to (or so as to) (effectively) sensitise cells involved with the proliferative disorder to killing induced by TNF.
- the SIK3 inhibitor may be administered in a therapeutically effective amount, such as an amount effective to sensitise the cells involved with the proliferative disorder to killing (cell- death) induced by TNF.
- the SIK3 inhibitor may be administered to the subject (for example, in an amount or dose effective) to induce apoptosis of such cells mediated by TNF, such as when such cells are in the presence of or contacted with TNF.
- the SIK3 inhibitor may be administered to the subject (eg in an amount or dose effective) to induce a reduced amount of cytotoxicity (eg apoptosis) - such as to not induce killing (eg apoptosis) of such cells - in the absence of TNF; for example the SIK3 inhibitor may be administered in an amount or dose that is - not as effective in cytotoxicity (eg apoptosis) - such as being not effective to induce such killing - in the absence of TNF.
- TNF can induce pro-apoptotic processes via binding to and/or signalling via tumour necrosis factor receptor 1 (TNFRl) and or tumour necrosis factor receptor 2 (TNFR2).
- the SIK3 inhibitor may be administered to the subject (eg in an amount or dose effective) to (effectively) sensitise cells involved with the proliferative disorder to apoptosis mediated by tumour necrosis factor receptor 1 (TNFRl) signalling and/or tumour necrosis factor receptor 2 (TNFR2) signalling.
- the SIK3 inhibitor can be administered to the subject (eg in an amount or dose effective) to (effectively) sensitise cells involved with the proliferative disorder to apoptosis mediated thereby in particular mediated by TNFRl.
- the SIK3 inhibitor may be administered in a therapeutically effective amount that is effective to mediate TNFRl- and/or TNFR2-sig nailing, and/or apoptosis mediated thereby.
- the SIK3 inhibitor may be administered (eg in an amount or dose effective) to induce apoptosis of such cells by TNFRl and/or TNFR2 signalling, such as upon active TNFRl signalling.
- the SIK3 inhibitor may be administered to the subject (eg in an amount or dose, such as a therapeutically effective amount) to (effectively) induce a reduced amount of cytotoxicity (eg apoptosis) - such as to not induce apoptosis of such cells - in the absence of TNFRl and/or TNFR2 signalling, such as in the absence of active TNFRl signalling.
- the SIK3 inhibitor may be administered in an amount or does that is not as effective in cytotoxicity (eg apoptosis) - such as being not effective to induce such apoptosis - in the absence of such signalling.
- the SIK3 inhibitor may be administered to the subject (eg in an amount or dose) to induce a reduced amount of cytotoxicity (eg apoptosis) - such as to not be cytotoxic - to cells involved with the proliferative disorder in the absence of the cell-mediated immune response.
- cytotoxicity eg apoptosis
- the SIK3 inhibitor may be continued to be administered to the subject even if the tumour of the subject is increased in size during treatment.
- an increase in tumour size during such treatment may indicate an (enhanced) immune reaction against cells of the tumour (eg, the cells have become sensitised to the cell-mediated immune response), and hence the administration of the SIK3 inhibitor can, in such embodiments, continued to be administered so as to maintain such sensitivity and associated (enhanced) immune reaction.
- the inventors herein demonstrate that the inhibition of SIK3 is associated with a number of key biological processes or phenotypes, including those surprisingly involved in the control and/or triggering of cytotoxic process innate to cells, such as apoptosis.
- tumour cells can be sensitised to the apoptotic effects of TNF by the inhibition of SIK3, acting through pathways and components thereof including liver kinase Bl (LKBl, STKll or NY-REN-19), histone deacetylase 4 (HDAC4), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB), and pro-apoptotic genes regulated by NF-kappaB such as Caspase 8 and Caspase 9.
- c-Jun N-terminal kinase JNK is a signalling component associated with sensitisation to the apoptotic effects of TNF by the inhibition of SIK3.
- the term "associated with”, in the context of this embodiment (and other embodiments, where applicable) can mean that two components, variables, effects or phenotypes are interrelated with each other, and/or that they are related to (eg correlated to) each other, and/or that there is a causative link between a first and a second component, variable, effect or phenotype (such as the second is in response to the first, the second is a consequence of the first, or the second is caused by the first).
- administration of the SIK3 inhibitor can associate with impairment of NF-kappaB activity (eg, by an enhancement or increase in translocation of NF-kappaB out of the nucleus) in cells involved with the proliferative disorder.
- such impairment of NF-kappaB activity may be associated with (activated) TNF- and/or TNFRl-mediated signalling (or TNFR2-mediated signalling) in such cells.
- the SIK3 inhibitor may be administered to the subject (eg in an amount or dose effective) to impair or inhibit NF-kappaB activity in the cells involved with the proliferative disorder, for example to enhance or increase translocation of NF-kappaB out of the nucleus of such cells.
- the SIK3 inhibitor may be administered to the subject in a (eg, therapeutically effective) amount being effective to (effectively) impair NF- kappaB activity in cells involved with the proliferative disorder, in particular in an amount effective to (effectively) enhance or increase translocation of NF-kappaB out of the nucleus of the cells involved with the proliferative disorder.
- administration of the SIK3 inhibitor may be associated with an increase in (eg, the SIK3 inhibitor is administered, such as in an amount or dose effective, to increase) activity of class II (eg Ila) HDACs, eg HDAC4, in the cells involved with the proliferative disorder, for example its translocation or localisation to or its activity in the nucleus of such cells; and in particular upon TNF- and/or TNFRl-mediated signalling (or TNFR2-mediated signalling) in such cells.
- class II eg Ila
- HDACs eg HDAC4
- TNF- and/or TNFRl-mediated signalling or TNFR2-mediated signalling
- administration of the SIK3 inhibitor may be associated with de- acylation of nuclear NF-kappaB (eg de-acylation at its p65 subunit) and/or decreased transactivation of one or more anti-apoptotic factors, in particular upon TNF- and/or TNFRl-mediated signalling (or TNFR2-mediated signalling) in the cells involved with the proliferative disorder.
- the SIK3 inhibitor may be administered (such as in an amount or dose effective) to cause de-acylation of nuclear NF-kappaB (eg at its p65 subunit) and/or decreased transactivation of one or more anti-apoptotic factors.
- administration of the SIK3 inhibitor may be associated with an increase in (eg the SIK3 inhibitor is administered, such as in an amount or dose effective, to increase) cleavage of Casapse 8 and/or Caspase 9 in the cells involved with the proliferative disorder, in particular upon TNF- and/or TNFRl-mediated (or TNFR2-mediated signalling) signalling in such cells.
- administration of the SIK3 inhibitor may be associated with a reduction in the transcription of one or more anti-apoptotic factors, in particular upon TNF- and/or TNFRl-mediated signalling (or TNFR2-mediated signalling) in the cells involved with the proliferative disorder, for example the reduction of the transcription of one or more NF-kappaB target genes in such cells.
- the SIK3 inhibitor is administered (eg in an amount dose effective) to reduce the transcription of one or more such anti-apoptotic factors, in particular upon TNF- and/or TNFRl-mediated signalling (or TNFR2-mediated signalling) in the cells involved with the proliferative disorder.
- the administration of the SIK3 inhibitor may be associated with an increase in (eg the SIK3 inhibitor is administered, such as in an amount or dose effective, to increase) JNK activation (such as by phosphorylation) in the cells involved with the proliferative disorder, in particular upon TNF- and/or TNFRl-mediated signalling (or TNFR2-mediated signalling) in such cells.
- an increase in eg the SIK3 inhibitor is administered, such as in an amount or dose effective, to increase
- JNK activation such as by phosphorylation
- administration of the SIK3 inhibitor may not be associated with a significant change in CREB-pathways signalling and/or a significant change gene expression mediated by CREB and/or CREB- regulation.
- the TNF- (TNFR2-) and/or TNFRl-mediated signalling in the cells involved with the proliferative disorder may be associated with increased levels of pLKBl in such cells.
- the treatment aspects of the invention may further comprise a step of administering one or more other moieties that appropriately modify the expression, activity, function or stability of one or more these other pathway components described above, so as to additively or synergistically contribute to the treatment effect.
- a treatment aspect of the invention may further comprise a step of administering an inhibitor of LKB1 (in particular, when the SIK3 inhibitor is not an inhibitor of LKB1).
- a treatment aspect of the invention may further comprise a step of administering a compound that promotes, enhances or increases one or more class II (eg Ila) HDACs (histone deacetylases), such as HDAC4, in the nucleus of the cells involved with the proliferative disorder.
- a treatment aspect of the invention may further comprise a step of administering an inhibitor of NF-kappaB (activation).
- activation an inhibitor of NF-kappaB
- the invention also envisions that combinations of two or more such other moieties may be used in a treatment together with the SIK3 inhibitor and/or using other (eg anti-cancer) therapeutically active agents together with the SIK3 inhibitor.
- the invention relates to a method for the sensitisation of cells involved with a proliferative disorder to a cell- mediated immune response, the method comprising exposing (eg contacting) the cells involved with a proliferative disorder to a SIK3 inhibitor.
- a method for the sensitisation of cells involved with a proliferative disorder to a cell- mediated immune response comprising exposing (eg contacting) the cells involved with a proliferative disorder to a SIK3 inhibitor.
- Such a method may, typically, be practiced as an in-vitro and/or ex-vivo method.
- the cell-mediated immune response comprises killing the cells involved with a proliferative disorder, such as where said killing is involves TNF, TNFR2- and/or TNFRl-mediated signalling.
- the killing of such cells may involve apoptosis of such cells induced by TNF, TNFR2- and/or TNFRl- mediated signalling.
- TNFR2- and/or TNFRl-mediated signalling may be triggered (eg activated) by any appropriate triggering molecule, such as TNF, a variant of TNF and or a TNFR2 or TNFR1 agonist; in particular by exposing (eg by contacting) the cells associated with the proliferative disorder to the triggering molecule (eg TNF, TNF variant or TNFR1 agonist).
- the triggering molecule eg TNF, TNF variant or TNFR1 agonist
- the triggering molecule eg TNF, TNF variant or TNFR1 agonist binding to TNFR2 and/or TNFR1 and, in particular the triggering (eg activation) of TNFR1 signalling
- the invention relates to a method for the killing of cells involved with a proliferative disorder, the method comprising exposing (eg contacting) the cell involved with the proliferative disorder to: (i) TNF, a TNF variant and/or an agonist of TNFR1- or TNFR2-signalling (preferably, TNFRl-signalling); and exposing (eg contacting) the cells involved with the proliferative disorder to (ii) a SIK3 inhibitor.
- TNF a TNF variant and/or an agonist of TNFR1- or TNFR2-signalling
- SIK3 inhibitor preferably, TNFRl-signalling
- the invention relates to a SIK3 inhibitor for use in the treatment of a proliferative disease involving the killing of a cell involved with the proliferative disorder, the treatment comprising exposing such cell to: (i) TNF, a TNF variant and/or a TNFR1 or TNFR2 agonist; and (ii) a SIK3 inhibitor.
- the killing of the cell involved with the proliferative disorder is mediated by sensitising such cell to a cell-mediated immune response, in particular by inducing sensitivity to apoptosis of such cell that involves TNF, TNFR2 and/or TNFRl-mediated signalling.
- the cell(s) involved with the proliferative disorder may be exposed to the TNF, a TNF variant and/or a TNFR1 or TNFR2 agonist by contacting the cell to such triggering molecule; and/or such cell(s) may be exposed to the SIK3 inhibitor by contacting (of introducing into) such cell(s) with the SIK3 inhibitor.
- the amounts (or dose) of (i) TNF, a TNF variant and/or a TNFR1 or TNFR2 agonist; and/or (ii) a SIK3 inhibitor are, typically, effective amounts; that is amounts (or doses) that are effective in, for example, sensitising the cell(s) to (such as killing such cell(s) by) apoptosis induced by TNF, TNFR2 and/or TNFRl-mediated signalling.
- suitable amounts of these active agents (or ways to determine them) that may be incorporated in these aspects of the invention; as are further particular characteristics of the SKI3 inhibitor.
- TNF, a TNF variant and/or a TNFR1 or TNFR2 agonist; and (ii) a SIK3 inhibitor can be administered to a subject suffering from the proliferative disorder (eg, the treatment can comprise the administration of: (i) TNF, a TNF variant and/or a TNFR1 or TNFR2 agonist; and (ii) a SIK3 inhibitor, can be administered to the subject).
- the treatment can comprise the administration of: (i) TNF, a TNF variant and/or a TNFR1 or TNFR2 agonist; and (ii) a SIK3 inhibitor, can be administered to the subject).
- the cell(s) involved with the proliferative disorder may be one as described elsewhere herein, and in particular such cell(s) may be cancerous or tumour cell.
- such cell(s) may be one that is of, or derived from, a solid tumour.
- the method is an in vitro (and/or ex-vivo) method.
- the cell(s) involved with the proliferative disorder (such as tumour cells) is present in such subject, in particular in a subject in need of treatment thereof.
- treatment effect of such method eg, on the cell(s) involved with the proliferative disorder
- the treatment may comprise, involve or be mediated by) inhibiting SIK3; in particular, by inhibiting the expression, amount, function, activity and/or stability of SIK3 mRNA or protein (eg, of phosphorylated SIK3 protein, and/or as described elsewhere herein).
- SIK3 activity is (eg, effectively) reduced, such as reduced to a therapeutically effective level.
- the (treatment) effect of such method may NOT be mediated by (eg, the treatment may NOT comprise, involve or be mediated by) inhibiting Abl and/or SRC kinase; by NOT (effectively) inhibiting the expression, amount, function, activity and/or stability of Abl and/or SRC kinase or protein.
- activity of the ABL1 and/or SRC is NOT (effectively) reduced, such as is NOT reduced to a therapeutically effective level.
- the cell(s) involved with the proliferative disorder are not killed or induced to enter apoptosis (for example, they proliferate) upon TNF, TNFR2- and/or TNFRl-mediated signalling and/or exposure to (eg, the effective amount or dose of) TNF, TNF variant, TNFR2 or TNFR1 agonist.
- the SIK3 inhibitor may inhibit SIK3 in (of) the cell(s) involved with the proliferative disorder (eg tumour cells).
- the SIK3 inhibitor may inhibit SIK3 in (of) such cell(s) preferentially to inhibiting SIKl and/or SIK2 in (of) such cell; and/or may inhibit SIK3 in such cell preferentially to inhibiting SIKl and/or SIK2 and/or SIK3 in (of) one or more types of immune cells.
- the SIK3 inhibitor may inhibit SIK3 in (of) the cell(s) involved with the proliferative disorder (eg tumour cells) preferentially to inhibiting SIKl and/or SIK2 and/or SIK3 in (of) macrophages and/or dendritic cells (in particular, those capable of or producing IL-10).
- the proliferative disorder eg tumour cells
- SIKl and/or SIK2 and/or SIK3 in (of) macrophages and/or dendritic cells (in particular, those capable of or producing IL-10).
- the (treatment) effect is mediated by (eg, the treatment comprises, involves or is mediated by) inhibition of SIK3 in (of) the cell(s) involved with the proliferative disorder (eg a tumour cell); and in further of such embodiments, the (treatment) effect is not mediated by (or the effect is mediated by not) (eg, the treatment does not comprise, involve or is not mediated by) inhibiting SIK2, in particular SIK2 in/of other cells (such as those involved with the proliferative disorder or immune cells), and/or the (treatment) effect is not mediated by (or the effect is mediated by not) inhibiting SIKl (eg, the treatment does not comprise, involve or is not mediated by inhibiting SIKl), in particular SIKl in/of other cells (such as those involved with the proliferative disorder or immune cells).
- SIK2 in particular SIK2 in/of other cells
- SIKl such as those involved with the proliferative disorder or immune cells
- the ABL and/or SRC in (of) other cells may NOT be inhibited.
- the SIK3 of (eg, in) the cell(s) involved with the proliferative disorder is inhibited.
- SIK2 in particular SIK2 of (eg in) immune cells - such as CTLs - is inhibited to a lesser extent than SIK3 (eg in the cell(s) involved with the proliferative disorder).
- SIKl in particular SIKl of (eg in) immune cells - such as CTLs - is inhibited to a lesser extent than such SIK3.
- a given SIK may be inhibited to a "lesser extent" than another SIK (such as SIK3) if, for example, the other SIK (such as SIK3) is inhibited by an amount greater than about 2 fold more than the given SIK, such as by an amount greater than about 5, 10, 20, 50, 75 or 100-fold more than the given SIK.
- the other SIK (such as SIK3) may be inhibited by an amount between about 5 and 20 fold, 20 and 50 or 50 and 100 fold more than the given SIK.
- the SIK3 may be inhibited between about 20 and 50 fold more than SIKl and/or SIK2.
- the SIK3 inhibitor may inhibit SIK3 by 80% (ie, to have only 20% of its uninhibited activity) but inhibit SIKl by only 4% and SIK2 by only 8%. Accordingly, SIK3 is inhibited about 20-fold more than SIKl and 10-fold more than SIK2.
- the SIK3 may be inhibited to about the same extent as SIKl (eg between about 2 to 53 fold of each other), and SIK2 is inhibited to a lesser extent that either (or both) of SIK3 and SIKl:
- SIK3 and SIKl are inhibited by between about a 20 and 50 fold more than SIK2 (eg in immune cells) is inhibited.
- treatment with the SIK3 inhibitors in accordance with the present invention may not be associated with an (effective) increase in the production of one or more anti-inflammatory cytokines (for example the anti-inflammatory cytokine may be one selected from the list consisting of: IL-lra, IL-4, IL-10, IL-11, IL-13 and TGF-beta), and in particular may not be associated with an (effective) increase in the production of IL-10.
- the anti-inflammatory cytokine may be one selected from the list consisting of: IL-lra, IL-4, IL-10, IL-11, IL-13 and TGF-beta
- treatment with the SIK3 inhibitors in accordance with the present invention may not be associated with an (effective) decrease in the production of one or more pro-inflammatory cytokines; for example, one selected from the list consisting of: IL-1- beta, IL-6, IL-12 and TNF, IFN-gamma and granulocyte-macrophage colony stimulating factor, and in particular embodiments may not be associated with an (effective) decrease in the production of TNF.
- pro-inflammatory cytokines for example, one selected from the list consisting of: IL-1- beta, IL-6, IL-12 and TNF, IFN-gamma and granulocyte-macrophage colony stimulating factor, and in particular embodiments may not be associated with an (effective) decrease in the production of TNF.
- the SIK3 inhibitor may be administered to a subject in: (i) a (therapeutically effective) amount NOT effective to (effectively) increase the production of one or more (eg such) anti-inflammatory cytokines; and/or (ii) in a (therapeutically effective) amount NOT effective to (effectively) decrease the production of one or more (eg such) pro-inflammatory cytokines.
- a (therapeutically effective) amount NOT effective to (effectively) increase the production of one or more (eg such) anti-inflammatory cytokines e.g such) anti-inflammatory cytokines
- a (therapeutically effective) amount NOT effective to (effectively) decrease the production of one or more (eg such) pro-inflammatory cytokines e.g tumour cells
- such cells may be those that exhibit (eg are subject to) activation of TNFR2 and/or TNFRl signalling, in particular an activated TNFRl.
- such cells are those that express TNFR2 and/or TNFRl, in particular tumour cells that express TNFRl.
- such cells are distinguished or characterised by activated TNFRl- and/or TNFR2-signalling (or the subject is distinguished or characterised by having cells involved with the proliferative disorder - eg tumour cells - that are so distinguished or characterised).
- the person of ordinary skill will know techniques for determining the status of TNFRl- and/or TNFR2- activation in such cells (such as of the subject). For example, by detecting or monitoring one or more down-stream protein in the TNFRl- and/or TNFR2-signalling pathways.
- proteins are described elsewhere herein, and include NF-kappaB and/or HDAC4.
- the invention relates to a method for the treatment of a proliferative disorder
- the (treatment) method comprising administering a SIK3 inhibitor to the subject, by inhibiting SIK3, wherein cells involved with the proliferative disorder are characterised by (eg exhibit or are subject to) activated TNFR2 and/or TNFRl signalling (eg activated TNFRl signalling).
- the invention relates to a SIK3 inhibitor for use in the treatment of a proliferative disorder, wherein cells involved with the proliferative disorder are distinguished or characterised by (eg exhibit or are subject to) activated TNFR2 and/or TNFRl signalling (eg activated TNFRl signalling).
- cells involved with the proliferative disorder are those exposed to an appropriate triggering or activating molecule, such as TNF, a variant of TNF and or an agonist of TNFR2- or TNFRl-signalling (preferably, an agonist of TNFRl-signalling), in particular are exposed to an effective amount of such triggering or activating molecule.
- an appropriate triggering or activating molecule such as TNF, a variant of TNF and or an agonist of TNFR2- or TNFRl-signalling (preferably, an agonist of TNFRl-signalling)
- the triggering or activating molecule when the triggering or activating molecule is TNF, it is human TNF.
- the TNF is recombinant human TNF (rHuTNF).
- the TNF is endogenous TNF, such as that is produced by or otherwise present in the subject (eg the human patient).
- TNF levels are elevated in numerous types of cancers, and that for example, the upper normal limit of total TNF in healthy subjects is 1.8 pg/mL, as measured using; a Quantikine human TNF-alpha Immunoassay PDTA00C, including in ovarian cancer (Dobrzycka et al 2009, Eur Cytokine Netw 20:131).
- a Quantikine human TNF-alpha Immunoassay PDTA00C including in ovarian cancer.
- TNF-alpha-EASIA Kit, DIAsource the TNF plasma levels of oesophageal cancer patients and the control group were 12.35 ⁇ 9.69 and 4.62 ⁇ 3.06 pg/ mL, respectively (Aydin et al 2012, Turk J Med Sci 42:762).
- the cells involved with the proliferative disorder are (for example a tumour is) one present in a subject having a plasma concentration of TNF greater than about 1.5, 2.5 or 4 pg/mL, such as greater than about 5 pg/mL, and in particular greater than about 10 pg/mL (for example, as measured by a Quantikine human TNF-alpha Immunoassay PDTA00C or a TNF-alpha-ELISA Kit, DIAsource).
- the subject involved in the treatment methods of the invention may have (that is, such a subject can be distinguished by, such as distinguished as one suitable for the therpapeutic methods of the present invention, by showing, posessing or displaying) a plasma concentration of TNF greater than about 2 pg/mL or greater than about 5 pg/mL (eg, the cells involved with the proliferative disorder are one present in a subject having a plasma concentration of TNF greater than about 2 pg/mL or 5 pg/mL).
- the intratumoural concentration of TNF may be a characterisation of the tumour, such as when the tumour is a solid tumour and accessible for biopsy (Reissfelder et al 2015, J Clin Inv 125:739).
- a tumour such as a solid tumour eg colorectal cancer
- a tumour tissue can, in some embodiments of the invention, have an intratumoural concentration (eg, within the tumour tissue) of TNF that is greater than about 0.2, 0.5 or 1 pg/mL, such as greater than about 2 pg/mL, and in particular greater than about 5 pg/mL (for example, as measured by a Quantikine human TNF-alpha Immunoassay).
- the solid tumour eg, within the subject
- the solid tumour may have (that is, such a subject can be distinguished by, such as distinguished as one suitable for the therpapeutic methods of the present invention, by showing, posessing or displaying) an intratumoural concentration of TNF greater than (about) 0.5 pg/mL or greater than about 1 pg/mL.
- the invention can relate to a method for the treatment of a proliferative disorder (or a SIK3 inhibitor for use in such a treatment) in a subject distinguished by having: (i) a plasma concentration of TNF greater than about 2 pg/mL (preferably greater than about 5 pg/mL); and/or (ii) an intratumoural concentration of TNF greater than about 0.5 pg/mL preferably greater than about 1 pg/mL), the treatment method comprising administering a SIK3 inhibitor to the subject, wherein the SIK3 inhibitor: (a) inhibits SIK3 in cells involved with the proliferative disorder; and/or (b) sensitises cells in the subject involved with the proliferative disorder to a cell-mediated immune response.
- the amount (or dose) of SIK3 inhibitor that is exposed to cells involved with the proliferative disorder, or that is administered to the subject is related to (eg correlated to) the plasma or intratumoural concentration of TNF, wherein a greater amount (or dose) of SIK3 inhibitor is exposed to such cells (or administered to such subject) in those cases of a greater plasma or intratumoural concentration of TNF.
- the tumour may be present in a subject having tumour-reactive T-cells in peripheral blood or bone marrow, for example as may be determined by INF-gamma ELISPOT.
- the tumour shows infiltration by Tregs, CD4+ Tconv and/or CD8+ T cells.
- the cells involved with the proliferative disorder comprises a single nucleotide polymorphism (SNP) in the promoter region of TNF associated increased expression of TNF and cancer sensitivity, for example with an M or GA genotype at the -308G/A SNP in the promoter region of TNF; and in alternative embodiments the tumour does not comprise a SNP associated with decreased expression of TNF and reduced cancer risk, such as does not comprise an M or GA genotype at the -238G/A SNP or a -857T allele, in each case in the promoter region of TNF (Wang and Lin 2008, Acta Pharmacol Sin 28:1275).
- SNP single nucleotide polymorphism
- the invention hereby provides alternative combination treatment regimens based on the surprising finding of the inventors that SIK3 activity can influence the sensitivity of a cell towards the cytotoxic effects of TNF.
- the invention relates to a method for the treatment of a proliferative disorder in a subject, the method comprising exposing (eg contacting) cells involved with the proliferative disorder in the subject to: (i) TNF, a TNF variant and/or an agonist of TNFR2- or TNFRl-signalling; and exposing (eg contacting) the cells involved with the proliferative disorder in the subject to (ii) a SIK3 inhibitor.
- step (i) of such method does not comprise exposing (eg contacting) cells involved with the proliferative disorder in the subject to a TNF variant.
- the proliferative disorder and/or such cells are those of the tumour, and in other embodiments, component (i) is TNF, in particular human TNF (such as rHuTNF); and/or component (i) is an agonist of TNFRl-signalling.
- component (i) is TNF, in particular human TNF (such as rHuTNF); and/or component (i) is an agonist of TNFRl-signalling.
- the method comprises (eg the treatment comprises, involves or is mediated by) increasing the amount of TNF exposed to the cells involved with the proliferative disorder in the subject.
- the treatment may comprise (eg, involves or is mediated by) increasing TNFR1- and/or TNFR2-signalling in (of) the cells involved with the proliferative disorder in the subject.
- the invention relates to a method for the treatment of a proliferative disorder in a subject, the method comprising: (i) increasing TNFR1- and/or TNFR2-signalling in (of) the cells involved with the proliferative disorder; and (ii) exposing (eg contacting) the cells involved with the proliferative disorder in the subject to a SIK3 inhibitor.
- the method can, for example, be effected though the consequence(s) of SIK3 inhibition (such as inhibition of the expression, amount, function, activity and/or stability of SIK3, eg of phosphorylated SIK3), in particular in combination with the consequence(s) of activation of TNFRl- and/or TNFR2-sig nailing, such as upon binding of the TNF, TNF variant and/or TNFRl agonist to TNFRl or TNFR2.
- SIK3 inhibition such as inhibition of the expression, amount, function, activity and/or stability of SIK3, eg of phosphorylated SIK3
- TNFRl- and/or TNFR2-sig nailing such as upon binding of the TNF, TNF variant and/or TNFRl agonist to TNFRl or TNFR2.
- the treatment effect can, in certain embodiments, involve, or be mediated (eg, caused) by, inhibiting SIK3, and/or by sensitising the cells involved with the proliferative disorder to the cytotoxic (eg apoptotic) effects of TNFRl- or TNFR2-signalling.
- the SIK3 activity may be (effectively) reduced, such as to a therapeutically effective level.
- SIK3 in the tumour cells is inhibited and, optionally, where SIK2 and/or SIK1 are inhibited to a lesser extent, such as SIK2 or SIK1 of immune cells.
- the treatment comprises, involves or is mediated by (eg, the SIK3 inhibitor is administered in an amount, such as a therapeutically effective amount that is effective to) inhibition of SIK3 activity such that it is (eg, effectively) reduced, such as reduced to a therapeutically effective level; and/or (y) the treatment comprises, involves or is mediated by (eg, the SIK3 inhibitor is administered in an amount, such as a therapeutically effective amount that is NOT effective to) inhibition of Abl and/or SRC kinase, such that Abl and/or SRC kinase activity is NOT (eg, effectively) reduced, such as is NOT reduced to a therapeutically effective level.
- the subject can be administered the SIK3 inhibitor and/or can be administered (the) TNF, and/the TNF variant or an/the agonist of TNFRl- or TNFR2-signalling.
- the SIK3 inhibitor and the TNF, TNF variant or TNFRl or TNFR2 agonist can be exposed to (for example administered in) an effective amount (or dose), including in formulations or administrative routes as described elsewhere herein.
- an effective amount or dose
- the TNF, TNF variant or TNFRl or TNFR2 agonist is encapsulated as a liposomal or other nanoparticle formulation.
- such combination treatment regimen may comprise embodiments where such exposures/administrations are concomitant.
- such exposures/administrations may be sequential; in particular those embodiments where the SIK3 inhibitor is exposed/administered before the TNF, TNF variant or TNFRl or TNFR2 agonist is exposed/administered.
- the SIK3 inhibitor may be sequentially exposed/administered within about 14 days of (eg before) the other component, such as within about 10 days, 7 days, 5 days, 2 days or 1 day of (eg before) the other component; and further including where the SIK3 inhibitor may be sequentially exposed/administered within about 48 hours, 24 hours, 12 hours, 8 hours, 6 hours, 4 hours, 2 hours, 1 hours, 30 mins, 15 mins or 5 mins of (eg before) the other component.
- the TNF or the TNF variant or TNFRl or TNFR2 agonist may be administered via conventional routes, such as s.c, i.v. or i.m., and on certain embodiments may be administered intratumourally or by isolated limb perfusion (ILP), such as isolated hepatic perfusion (IHP); and/or may be so administered (in particular, rHuTNF may be so administered) at a dose of between about 5 and 500 ug/m2/day.
- IHP isolated limb perfusion
- TNF may be administered between about 25 and 250 ug/m2/day, such as between about 50 and 150 ug/m2/day or between about 75 and 100 ug/m2/day; or wherein TNF is administered up to a MTD of about 50 and 75 ug/m2/day when administered s.c. or up to a MTD of about 150 and 200 ug/m2/day when administered i.v. or i.m.
- TNF can be administered to the subject at a dose of between about 5 and 500 ug/m2/day, in particular between about 20 and 200 ug/m2/day.
- a variant of TNF such as a TNF variant having higher anti-tumour activity and lower systemic toxicity that rHuTNF may be exposed/administered.
- the TNF variant may be one selected from the group consisting of: (i) a -K90R variant of TNF; (ii) a tumour-homing peptide conjugated to TNF; and (iii) a TNF-antibody conjugate.
- TNF variant in those embodiments of the invention involving a TNF variant, it may be a variant form of TNF having higher cytotoxic activity and lower systemic toxicity.
- a TNFRl or TNFR2 agonist such as the anti-TNFRl monoclonal antibody htr-9 (Ferrero et al 2001, Am J Physiol Cell Physiol 281:C1173) may be exposed/administered, and in other embodiments lymphotoxin-alpha (Etemadi et al 2013, FEBS J 280:5283) or a variant thereof may be exposed/administered.
- cells involved with the proliferative disorder may be exposed to TNF (or increased TNFRl- and/or TNFR2-signalling) through the administration of an agent (eg to a subject harbouring such cell) that can lead to the exposure of such cells to (eg endogenous) TNF, or to another triggering molecule such as a variant of TNF or a TNFRl or TNFR2 agonist.
- an agent eg to a subject harbouring such cell
- TNF eg endogenous TNF
- another triggering molecule such as a variant of TNF or a TNFRl or TNFR2 agonist.
- Such an agent may, for example, be one that is capable of inducing (eg induces) the exposure of such cells to (eg an elevated level of) TNF, in particular an agent that induces the exposure of such cells to TNF levels, such as to an effective amount of (eg endogenous) TNF, for example levels of plasma or intratumoural TNF that are greater than one or those levels described elsewhere herein.
- the invention includes those embodiments wherein the subject is administered an agent that is capable of inducing (eg induces) the exposure of the cells involved with the proliferative disorder to (the) TNF, an/the TNF variant or an/the agonist of TNFRl- or TNFR2-signalling.
- the invention also includes those embodiments wherein the subject gets administered an agent that is capable of increasing TNFRl-signalling (and/or TNFR2- signalling) of, and/or increasing the amount of TNF exposed to, cells involved with the proliferative disorder in the subject.
- the agent is a virus, in particular one that has been engineered to produce a triggering molecule being TNF, a TNF variant or the TNFRl or TNFR2 agonist (especially, a virus engineered to produce human TNF).
- a virus preferentially infects the cell(s) involved with the proliferative disorder (eg tumour cells) and/or preferentially produces the triggering molecule in the context of (eg when it infects) such cells.
- the administration of such a virus can lead to the exposure of the cell(s) involved with the proliferative disorder to such triggering molecule, and in particular to an effective amount of such a triggering molecule such as TNF.
- the agent may be a virus that is capable of inducing (eg induces) the exposure of the cell(s) involved with the proliferative disorder the TNF, TNF variant or agonist or TNFRl- or TNFR2-sig nailing.
- Such a virus may be any that is suitable for inducing the exposure of the triggering molecule, and in particular may be a recombinant virus; for example one engineered to infect tumour cells and/or to express TNF (eg after infecting a tumour cell).
- virus that may be so engineered include oncolytic viruses (eg, those based on an adenovirus, HSV, vaccinia virus, vesicular stomatitis virus or Newcastle disease virus), such as intratumoural injection of adenovirus vectors to increase plasma levels of pro-inflammatory cytokines and chemokines, including TNF (Bernt et al 2005, Cancer Res 65:4343).
- the oncolytic virus may be one based on a DNA virus described in Table 1 of Kaufman et al 2015 (Nature Rev Drug Disc 14:642), one based on an RNA virus described in Table 2 of Kaufman et al 2015, preferably, is an oncolytic virus described in Table 3 of Kaufman et al 2015 as being in clinical trials.
- the agent that is administered (and that consequentially leads to exposure of the cells involved with the proliferative disorder to a triggering molecule being TNF, a TNF variant or a TNFRl or TNFR2 agonist) is an immune cell.
- the immune cell may not be an ILlO-producing macrophage, for example the immune cells can be a pro-inflammatory immune cell.
- the immune cell that is administered may be a lymphoid cell, eg a T cell or a natural killer (NK) cell, for example such a cell that produces TNF.
- the immune cell When administered as an agent in such embodiments of the invention, the immune cell may be administered via adoptive cell transfer (ACT); meaning the transfer of the immune cell into the subject (eg, by infusion or other delivery techniques).
- ACT adoptive cell transfer
- Such process is, typically, conducted with the goal of improving immune functionality and characteristics in the subject, and while conventionally the transferred immune cells will have originated from the same subject, they may alternatively have been derived from another (suitable) individual.
- the immune cells may be T cells extracted from the subject, genetically modified and cultured in vitro and returned to the same subject, such as in a therapeutic method of the invention.
- Such genetic modification can include those that enhance the specificity or targeting of the immune cell, such as the targeting of the immune cell (eg increasing its specificity) to the cell(s) involved with the proliferative disorder (eg a tumour cell).
- a T cell that is used in such embodiments may be modified to alter the specificity of the T cell receptor (TCR) or to introduce antibody-like recognition in chimeric antigen receptors (CARs).
- TCR T cell receptor
- CARs chimeric antigen receptors
- CAR immune cells are immune cells displaying engineered receptors, which graft an arbitrary specificity (eg to a tumour cell) onto an immune effector cell (eg a T cell). Typically, these receptors are used to graft the specificity of a monoclonal antibody onto a T cell; with transfer of their coding sequence facilitated by retroviral vectors.
- CAR T cells are a promising therapy for cancer (Song et al 2015, Oncotarget. 6:21533): using ACT, T cells are removed from an individual (typically the subject) and modified so that they express receptors specific to the patient's particular cancer.
- T cells which can then recognise the subject's cancer cells, are (re)introduced into the subject, leading to exposure of TNF (eg produced by the CAR T cells) to the tumour cells and hence killing of such cells, in particular such cells that are sensitised to such TNF-mediate cytotoxicity by exposure to (eg following administration to the subject of) a SIK3 inhibitor.
- the immune cells can be a CAR T cell, such as one engineered to have increased specificity to the subject's cells that are involved with the proliferative disorder (such as tumour cells).
- the exposure of the cells involved with the proliferative disorder to TNF may be induced by other means or procedures.
- the exposure of the cells involved with the proliferative disorder to (eg an effective amount of) TNF can be induced by (and/or the increase in TNFRl-signalling (and/or TNFR2-sig nailing) in/of the cells involved with the proliferative disorder is induced by) a pharmaceutical, therapeutic or other procedure that increases the amount of TNF in the plasma of the subject and/or in the environment of such cells.
- such induced exposure to TNF may be brought about by the administration of a cancer immunotherapy.
- an anti-tumour vaccine eg, a cancer vaccine
- Such cancer vaccines include those whereby antigens (eg, those specific to or preferentially expressed by cancer cells) are directly or indirectly introduced into the subject so as to raise or increase an immune response (typically, an adaptive immune response) in the subject that is envisioned to be (more) specific to the cancer cell.
- Cancer vaccine may comprise, for example, attenuated viruses, in particular for use against cancers such as cervical or liver cancers that are caused by such virus (eg HPV or HBV).
- Cancer vaccines can alternatively represent individual (or combinations) of particular tumour antigens (eg, those specific to or preferentially expressed by cancer cells), such as tumour-associated antigens (TAAs) that are used to immunise the subject so as to also raise or increase the immune response in the subject.
- TAAs tumour-associated antigens
- the cancer vaccine may comprise recombinant protein representing (eg a peptide from) the TM(s), or may be a tumour specific carbohydrate antigen, and hence are directly introduced into the subject upon administration.
- the cancer vaccine may, alternatively, comprise a nucleic acid (such as DNA or mRNA) than encodes the protein (or peptide) TAA, and upon administration of the nucleic acid vaccine into the subject, the encoded TAA is expressed by cellular targets in the subject, and hence are indirectly introduced into the subject.
- TAAs may be divided into two categories: shared tumour antigens; and unique tumour antigens. Shared antigens are expressed by many tumours. Unique tumour antigens result from mutations induced through physical or chemical carcinogens (also known as neoantigens); they are therefore expressed only by individual tumours.
- cancer vaccines in clinical trials, or approved for use, and include PROSTVAC (BavarianNordic), PROVENGE (Dendreon) and CV9104 (CureVac), as well as being aware of various TAAs (including neoantigens) and approaches by such tumour antigens may be utilised in cancer vaccines.
- PROSTVAC BorianNordic
- PROVENGE Dendreon
- CV9104 CureVac
- immunisation with recipient-derived clonal myeloma immunoglobulin, idiotype (Id), as a tumour antigen, conjugated with keyhole limpet hemocyanin (KLH) has been shown to produce substantial amount or proinflammatory cytokines including TNF (Foglietta et al 2013, Bone Marrow Transplant 48: 269); and (2) a synthetic micro-consensus SynCon DNA vaccine of WT1 antigens induced new, neo-antigen-like responses that were superior to those induced by native WT1 DNA immunogens, such as strong CD4 and CD8 T cell responses (including IFN- gamma, CD107a, and TNF responses).
- such induced exposure to TNF may be brought about by the administration of ligand (such as an antibody, eg, a monoclonal antibody), for example one that binds to the surface of the cell(s) involved with the proliferative disorder (such as a tumour cell), for example by binding to a TAA or a receptor on the surface of such cell.
- ligand such as an antibody, eg, a monoclonal antibody
- Cell surface receptors are common targets for such ligand (antibody) therapies and include CD52 and CD20.
- the eg antibodies can induce antibody-dependent cell-mediated cytotoxicity, activate the complement system, or prevent a receptor from interacting with its ligand, all of which can lead to cell death.
- ligands that are antibodies include alemtuzumab, ofatumumab and rituximab.
- such ligands used in combination with SIK3 inhibitors can include those that activate T cells or other cell-mediated immune response.
- anti-CD137 monoclonal antibodies can dramatically promote proliferation of cytokine- induced killer (CIK) cells and expression of TNF (Zhu et al 2009, Biomed Pharmacother 63:509)
- an agonist anti-OX40 monoclonal antibody can enhance antitumour immune response by augmenting T- cell differentiation (Redmond et al 2014, Cancer Immunol Res. 2014, 2:142)
- the ligand that is administered to the subject is one that binds to an immune (inhibitory) checkpoint molecule.
- checkpoint molecule may be one selected from the group consisting of: A2AR, B7-H3, B7-H4, CTLA-4, IDO, KIR, LAG3, PD-1 (or one of its ligands PD-L1 and PD-L2), TIM-3 (or its ligand galectin-9), TIGIT and VISTA.
- the ligand binds to a checkpoint molecule selected from: CTLA-4, PD-1 and PD-L1.
- the ligand is an antibody selected from the group consisting of: ipilimumab, nivolumab, pembrolizumab, BGB-A317, atezolizumab, avelumab and durvaluma; in particular an antibody selected from the group consisting of: ipilimumab (YERVOY), nivolumab (OPDIVO), pembrolizumab (KEYTRUDA) and atezolizumab (TECENTRIQ).
- the ligand that binds to a immune (inhibitory) checkpoint molecule may be a non-antibody peptide, such as a high-affinity PD-1 variant (eg, Maute et al, 2015; PNAS 112:E6506), a peptide targeting the immune checkpoint molecule (such as AUNP-12 of Aurigene Discovery Technologies, US 2011/0318373) or a D peptide blocking an interaction between immune checkpoint molecule (such as the PDL1-PD1 interaction and (D) PPA-1, Chang et a I, 2015; Anyeg Chem Int 54:11760).
- a non-antibody peptide such as a high-affinity PD-1 variant (eg, Maute et al, 2015; PNAS 112:E6506), a peptide targeting the immune checkpoint molecule (such as AUNP-12 of Aurigene Discovery Technologies, US 2011/0318373) or a D peptide blocking an interaction between immune checkpoint molecule (
- the ligand that binds to a immune (inhibitory) checkpoint molecule may be a small molecule, such as the PDLl-targeting BMS-202 or BMS-8 (Zak et al ,2016; Oncotarget 7:30323), the inhibitors of PDL1/D1 known as BMS-1001 or BMS-1166 (Skalniak et a I, 2017; Oncotarget 8:72167), the PDL1 and VISTA antagonist CA-170 of Curis/Aurigen undergoing phase 1 trials (Powderly et a I, Ann One 28: Issue suppl 5, mdx376.007) or CA-327 of Curis/Aurigen which targets PDL1 and TIM3.
- such induced exposure to TNF may be brought about by radiotherapy.
- Radiotherapy is a method of locoregional treatment of cancers or tumours, using radiation to destroy the cancer cells by blocking their ability to multiply and/or to stimulate an immune reaction against the them (such one raised as a response to the presence of dead or dying cancer cells).
- Radiotherapy in the context of the present invention, consists - in particular - of the therapeutic use of ionising radiation. Said radiotherapy and the associated ionising radiation are those commonly used and known to those skilled in the art.
- Radiotherapy includes in particular the use of ionizing radiation, for example gamma-rays, X-rays and/or radiation emanating from radioisotopes. In the context of the present invention, it is more particularly X-ray radiation.
- the radiotherapy may be administered in fractionated form during one or more cycles, such as a cycle that can range from 1 to 4 weeks, more particularly 3 weeks.
- the cycle defines the interval between the beginning and the end of an administration scheme.
- radiotherapy can be administered over three weeks, with one week between.
- the radiotherapy may in particular be administered at a rate of one daily irradiation, 5 days out of 7, for the desired number of weeks.
- the amount of radiation used in (photon) radiation therapy is measured in gray (Gy), and varies depending on the type and stage of cancer being treated.
- the typical dose for a solid epithelial tumour ranges from 60 to 80 Gy, while lymphomas are treated with 20 to 40 Gy.
- such combination treatment regimen may comprise embodiments where such exposures/administrations are concomitant.
- administrations may be sequential; in particular those embodiments where the SIK3 inhibitor is administered before such other procedure.
- the SIK3 inhibitor may be sequentially administered within about 14 days of (eg before) the other procedure, such as within about 10 days, 7 days, 5 days, 2 days or 1 day of (eg before) the other procedure; and further including where the SIK3 inhibitor may be sequentially administered within about 48 hours, 24 hours, 12 hours, 8 hours, 6 hours, 4 hours, 2 hours, 1 hours, 30 mins, 15 mins or 5 mins of (eg before) the other procedure.
- SIK3 inhibitor and hence inhibition of the expression, amount, function, activity or stability of SIK3, eg in a tumour cell
- administration of the TNF, TNF variant or TNFRl or TNFR2 agonist, or prior to administration of such other procedures eg, the other agent, the cancer immunotherapy, the cancer vaccine, the antibody or the radiotherapy, is foreseen to be particularly effective in sensitising the cells involved with the proliferative disorder to the cytotoxic effects of the cell-mediated immune response.
- the invention relates to a method for the increase of the therapeutic index of treatment with TNF in a subject being treated therewith for a proliferative disorder (eg a cancer disease or a tumour), the method comprising administering an inhibitor of SIK3 to the subject.
- a proliferative disorder eg a cancer disease or a tumour
- the invention relates to a method for supporting TNF therapy in a subject suffering from a proliferative disorder (eg a cancer disease or a tumour), the method comprising administering an inhibitor of SIK3 to the subject.
- a proliferative disorder eg a cancer disease or a tumour
- the invention relates to a method for the sensitisation of a subject suffering from a proliferative disorder (eg a cancer disease or tumour) to a therapy involving the administration of TNF to the subject, the method comprising administering an inhibitor of SIK3 to the subject.
- a proliferative disorder eg a cancer disease or tumour
- SIK3 an inhibitor of SIK3 to the subject.
- a subject that is so sensitised may, when undergoing such therapy, show an increased response (such as more rapidly, a greater degree of response and/or upon a lower amount or exposure of such therapy) than an analogous subject that have not been so "sensitised.
- the invention relates to a method for the reduction in risk of (developing) a haematological proliferative disorder (as a secondary disorder) in a subject being treated with an anti-TNF agent, the method comprising administering an inhibitor of SIK3 to the subject.
- a haematological proliferative disorder as a secondary disorder
- the method comprising administering an inhibitor of SIK3 to the subject.
- This aspect of the invention is based on the observation as described above, that there are reports of patients receiving anti-TNF biologies developing lymphomas and other haematological malignancies. Indeed, such disorders are typically described in package leaflets/pprescribing information as possible (but rare) side-effects of treatment with anti-TNF agents. As a direct consequence of the perceived increase in haematological malignancy and widespread use of these and other immunosuppressive agents, the WHO classification of tumours now includes the category "iatrogenic immunodeficiency-associated lymphoproliferative disease".
- the subject is being treated with the anti-TNF agent for an indication other than a proliferative disorder, and in particular of such embodiments the subject does not - upon commencement of the anti-TNF treatment - suffer from a haematological proliferative disorder.
- an autoimmune disorder selected from the group consisting of: rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, plaque psoriasis, inflammatory bowel disease, ulcerative colitis, Crohn's Disease, psoriasis, hidradenitis suppurativa and refractory asthma; such as one selected from the group consisting of: rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, plaque psoriasis and Crohn's Disease; and in particular rheumatoid arthritis.
- the anti-TNF agent is one selected from a list consisting of: infliximab, adalimumab, golimumab, humicade, etanercept, onercept and certolizumab pegol, in particular infliximab or humicade.
- the haematological malignancies proliferative disorder may be a lymphoproliferative disease, in particular an iatrogenic immunodeficiency-associated lymphoproliferative disease.
- the (treatment) effect is mediated by (eg, the treatment comprises or involves): (i) inhibiting SIK3 (such as by the inhibition of the expression, amount, function, activity and/or stability of SIK3, for example, of phosphorylated SIK3), in particular by inhibiting SIK3 in cells involved with the proliferative disorder; and/or (ii) sensitising such cells to the killing effects of TNF.
- SIK3 such as by the inhibition of the expression, amount, function, activity and/or stability of SIK3, for example, of phosphorylated SIK3
- the (treatment) effect may not be mediated by (eg, the treatment may not comprise or involve) inhibiting SIK2 and/or SIK1, in particular not mediated by (eg, the treatment does not comprise or involve) inhibiting SIK2 and/or SIK1 (and/or SIK3) in immune cells.
- SIK3 inhibitors of or for use with the invention are:
- the SIK3 inhibitor can be specific (eg, selective) for SIK3 (eg a SIK3-specific inhibitor).
- the SIK3 inhibitor may inhibit (eg the expression, amount, function, activity and/or stability of) SIK3 (in particular, the function or activity of phosphorylated SIK3) more potently than it inhibits (eg the expression, amount, function, activity and/or stability of) one or more other kinases, such as SIK2 and/or SIKl (in particular, the function or activity of phosphorylated SIK2 and/or phosphorylated SIKl), and /or ABL or SRC kinase.
- the SIK3 inhibitor inhibits SIK3 more potently than it inhibits ABL1 and/or SRC kinase.
- a SIK3 inhibitor can be considered “specific” (eg, “selective") for SIK3 or to inhibit SIK3 "more potently” if the SIK3 inhibitor inhibits SIK3 preferentially to inhibiting SIK2 and/or than SIKl.
- the SIK3 inhibitor inhibits SIK3 preferentially to inhibiting one or more other serine tyrosine kinases (STK), including without limitation Abl, Src and/or Bcr-Abl.
- STK serine tyrosine kinases
- a SIK3-specific inhibitor may inhibit SIK3 with a potency that is greater than about 2 fold more than its potency against the given other SIK (or STK), such as with a potency that is greater than about 5, 10, 20, 50, 100, 200, 500 or 1000 fold more potent than against the given other SIK (or STK).
- the SIK3 inhibitor may be more potent against SIK3 by an amount between about 50 and 500 fold, 10 and 200 fold or 50 and 1000 fold more than its potency against the given other SIK (or STK).
- the SIK3 inhibitor may be more potent against SIK3 by an amount that is between about 20 and 500 fold more potent than against SIKl and/or against SIK2.
- the SIK3 inhibitor shows an IC50 for SIK3 inhibition that is lower than the IC50 for SIKl and or SIK2 inhibition, such as by a fold-amount (or range thereof) as described in this paragraph.
- the SIK3 inhibitor may inhibit SIK3 with an IC50 of about 2nM, but inhibit SIKl with an IC50 of only ⁇ and SIK2 with an IC50 of only 200nM. Accordingly, such SIK3 inhibitor inhibits SIK3 50-fold more potently than SIKl and 100-fold more potently than SIK2.
- the SIK3 inhibitor inhibits SIK3 in cells involved with a proliferative disorder.
- the SIK3 inhibitor inhibits such SIK3 more potently than it inhibits SIKl and/or SIK2 in such cells, and/or more potently than it inhibits SIKl and/or SIK2 and/or SIK3 (in particular, SIK2) in immune cells.
- the SIK3 inhibitor may inhibit SIK3 as well as another SIK; in particular of such embodiments the SIK3 inhibitor may inhibit SIK3 and SIKl more potently than inhibiting SIK2.
- the SIK3 inhibitor may inhibit SIK3 and SIKl at about the same potency (such as within about 2 and 5 fold of each other) but may inhibit SIK3 (and SIKl) more potently than it inhibits SIK2 (such as by an amount greater than about 5, 10, 20, 50, 100, 200, 500 or 1000 fold more).
- the SIK3 inhibitor may inhibit SIK3 and SIKl in cells involved with a proliferative disorder; optionally, more potently than it inhibits SIK2 in such cells, and/or more potently than it inhibits SIK2 in immune cells.
- Such specificity (selectivity or preferential potency) for SIK3 (and optionally, SIKl) or other kinases, such as ABL and/or SRC kinases, can be measured in-vitro, such as in an in vitro biochemical assay, for example as provided by DiscoverX, ProQinase, Reaction Biology or ThermoFisher.
- the specificity (selectivity or preferential potency) for SIK3 is measured in-vivo, such as in a cell-based or animal model.
- the SIK3 inhibitor in a cell-based of animal model, can inhibit (eg the expression, amount, function, activity and/or stability of) SIK3 (in particular, the function or activity of phosphorylated SIK3) in cells involved with a proliferative disorder, more potently than it inhibits (eg the expression, amount, function, activity and/or stability of) ABL and/or SRC kinases, and/or SIK2 (and/or SIKl) - in particular, the function or activity of phosphorylated SIK2 and/or phosphorylated SIKl; and/or SIK3 - cells (such as in (of) immune cells, or for ABL, SRC and SIK2, in/of cells involved with the proliferative disorder), preferably SIK2 in immune cells.
- SIK3 in immune cells involved with a proliferative disorder
- the (treatment) effect may be mediated by (eg, the treatment may comprise, involve or be mediated by) inhibition of (eg the expression, amount, function, activity and/or stability of) SIK3 (such as in cells involved with a proliferative disorder) and not by the inhibition of (eg the expression, amount, function, activity and/or stability of) ABL and/or SRC kinases, and/or SIK2 (and/or SIK3) - such as in an immune cell - in particular, the (treatment) effect may optionally be additionally mediated by (eg, the treatment may comprise, involve or be mediated by) inhibition of SIK1 in such cells.
- SIK3 such as in cells involved with a proliferative disorder
- the SIK3 inhibitor inhibits SIK3 in (of) cells involved with the proliferative disorder more potently than it inhibits ABL1 and/or SRC kinase in (of) such cells, and (preferably) more potently than it inhibits SIK2 and/or SIK1 in (of) such cells.
- the SIK3 inhibitor inhibits a kinase target of dasatinib (such as Abl, Src and/or Bcr- Abl with an IC50 that is less than dasatinib inhibits such target, for example by a factor of about 2, 3, 5 or 10-fold less.
- dasatinib such as Abl, Src and/or Bcr- Abl with an IC50 that is less than dasatinib inhibits such target, for example by a factor of about 2, 3, 5 or 10-fold less.
- the SIK3 inhibitor may be one selected from a polypeptide, peptide, glycoprotein, a peptidomimetic, an antibody or antibody-like molecule (such as an intra-body); a nucleic acid such as a DNA or RNA, for example an antisense DNA or RNA, a ribozyme, an RNA or DNA aptamer, siRNA, shRNA and the like, including variants or derivatives thereof such as a peptide nucleic acid (PNA); a genetic construct for targeted gene editing, such as a CRISPR/Cas9 construct and/or guide RNA/DNA (gRNA/gDNA) and/or tracrRNA; a hetero-bi-functional compound (such as a PROTAC or a HyT molecule); a carbohydrate such as a polysaccharide or oligosaccharide and the like, including variants or derivatives thereof;
- a nucleic acid such as a DNA or RNA, for example an antisense DNA or RNA
- the SIK3 inhibitor of the invention may be in a prodrug form.
- Prodrugs forms of a particular compound are those other compounds (such as ester forms of the particular compound) that upon administration to a subject undergo chemical conversion under physiological conditions to provide the particular compound.
- prodrugs can be converted to the particular compound by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the particular compound when, for example, placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
- Exemplary prodrugs are esters or amides which are hydrolysable in vivo.
- the SIK3 inhibitor is a nucleic acid.
- nucleic acid refers to DNA molecules (e.g., cDNA or genomic DNA), RNA molecules (e.g., mRNA), analogues of the DNA or RNA generated using nucleotide analogues (e.g., peptide nucleic acids and non-naturally occurring nucleotide analogues), and hybrids thereof.
- the nucleic acid molecule can be single-stranded or double-stranded.
- SIK3 inhibitors being CRISPR/Cas9 constructs and/or guide RNA/DNAs (gRNA/gDNA) and/or tracrRNAs
- the basic rules for the design of CRISPR/Cas9 mediated gene editing approaches are known to the skilled artisan and for example reviewed in Wiles MV et al (Mamm Genome 2015, 26:501) or in Savic N and Schwank G (Transl Res 2016, 168:15).
- the SIK3 inhibitor may be an inhibitory nucleic acid molecule, such as antisense nucleotide molecule including a siRNA or shRNA molecule, for example as described in detail herein below.
- the inhibitory nucleic acid can bind to, such as specifically bind to, a nucleic acid (such as mRNA) that encodes or regulates the expression, amount, function, activity or stability of: (i) SIK3 (eg phosphorylated SIK3); or (ii) a gene (such as LKB1 or the glucagon receptor) that controls the expression, amount, function and/or stability of SIK3 and, for example, thereby modulates the expression, amount function, activity and/or stability of SIK3 (eg phosphorylated SIK3).
- SIK3 eg phosphorylated SIK3
- a gene such as LKB1 or the glucagon receptor
- An inhibitor of SIK3 that is a nucleic acid can be, for example, an anti-sense nucleotide molecule, an RNA, DNA or PNA molecule, or an aptamer molecule.
- An anti-sense nucleotide molecule can, by virtue of it comprising an anti-sense nucleotide sequence, bind to a target nucleic acid molecule (eg based on sequence complementarity) within a cell and modulate the level of expression (transcription and/or translation) of SIK3, or it may modulate expression of another gene that controls the expression, function and/or stability of SIK3.
- an RNA molecule such as a catalytic ribozyme, can bind to and alter the expression of the SIK3 gene, or it can bind to and alter the expression of other genes that control the expression, function and/or stability of SIK3, such as a transcription factor for or repressor protein of SIK3 and/or LKB1 or the glucagon receptor.
- An aptamer is a nucleic acid molecule that has a sequence that confers it an ability to form a three-dimensional structure capable of binding to a molecular target.
- RNA interference is a process of sequence-specific gene silencing by post-transcriptional RNA degradation or silencing (prevention of translation). RNAi is initiated by use of double- stranded RNA (dsRNA) that is homologous in sequence to the target gene to be silenced.
- dsRNA double- stranded RNA
- RNAi double-stranded RNA
- dsRNA double-stranded RNA
- RNAi contains sense and antisense strands of about 21 contiguous nucleotides corresponding to the gene to be targeted that form 19 RNA base pairs, leaving overhangs of two nucleotides at each 3'end (Elbashir et al., Nature 411:494-498 (2001); Bass, Nature 411:428-429 (2001); Zamore, Nat. Struct. Biol. 8:746-750 (2001)).
- dsRNAs of about 25-30 nucleotides have also been used successfully for RNAi (Karabinos et al., Proc. Natl. Acad. Sci. USA 98:7863-7868 (2001).
- dsRNA can be synthesised in vitro and introduced into a cell by methods known in the art.
- a particularly preferred example of an antisense molecule of the invention is a small interfering RNA (siRNA) or endoribonuclease- prepared siRNA (esiRNA).
- siRNA small interfering RNA
- esiRNA endoribonuclease- prepared siRNA
- An esiRNA is a mixture of siRNA oligos resulting from cleavage of a long double-stranded RNA (dsRNA) with an endoribonuclease such as Escherichia coli RNase III or dicer.
- esiRNAs are an alternative concept to the usage of chemically synthesised siRNA for RNA Interference (RNAi).
- RNAi RNA Interference
- An esiRNAs is the enzymatic digestion of a long double stranded RNA in vitro.
- a modulator of the invention that is an RNAi molecule may bind to and directly inhibit or antagonise the expression of mRNA of SIK3.
- a modulator of the invention that is an RNAi molecule may bind to and inhibit or antagonise the expression of mRNA of another gene that itself controls the expression (or function or stability) of SIK3.
- Such other genes may include transcription factors or repressor proteins or LKB1 or the glucagon receptor.
- sequence identity of the antisense molecule according to the invention in order to target a SIK3 mRNA is with increasing preference at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99% and 100% identity to a region of a sequence encoding the SIK3 protein, as disclosed herein (or of such other controlling gene, of which a preferred example is the LKB1 gene).
- the region of sequence identity between the target gene and the modulating antisense molecule is the region of the target gene corresponding to the location and length of the modulating antisense molecule.
- sequence identity over a region of about 19 to 21bp of length corresponding to the modulating siRNA or shRNA molecule.
- Means and methods for determining sequence identity are known in the art.
- the BLAST Basic Local Alignment Search Tool
- preferred antisense molecules such as siRNAs and shRNAs of the present invention are preferably chemically synthesised using appropriately protected ribonucleoside phosphoramidites and a conventional RNA synthesiser.
- RNA synthesis reagents include Proligo (Hamburg, Germany), Dharmacon Research (Lafayette, CO, USA), Pierce Chemical (part of Perbio Science, Rockford, IL (USA), Glen Research (Sterling, VA, USA), ChemGenes (Ashland, MA, USA), and Cruachem (Glasgow, UK).
- Liposome based and polymer- based nanoparticle approaches comprise the cationic lipid Genzyme Lipid (GL) 67, cationic liposomes, chitosan nanoparticles and cationic cell penetrating peptides (CPPs).
- Conjugated or complexation pharmaceutical compositions comprise PEI-complexed antisense molecules, siRNA, shRNA or miRNA.
- viral delivery systems comprise influenza virus envelopes and virosomes.
- the antisense molecules, siRNAs, shRNAs may comprise modified nucleotides such as locked nucleic acids (LNAs).
- LNAs locked nucleic acids
- the ribose moiety of an LNA nucleotide is modified with an extra bridge connecting the 2' oxygen and 4' carbon. The bridge "locks" the ribose in the 3'-endo (North) conformation, which is often found in the A-form duplexes.
- LNA nucleotides can be mixed with DNA or RNA residues in the oligonucleotide whenever desired. Such oligomers are synthesised chemically and are commercially available.
- the locked ribose conformation enhances base stacking and backbone pre-organisation.
- GapmeR LNATM GapmeRs (Exiqon)
- GapmeRs are potent antisense oligonucleotides used for highly efficient inhibition of SIK3 mRNA (or of mRNA of a gene controlling expression, function and/or sta-bility of SIK3).
- GapmeRs contain a central stretch of DNA monomers flanked by blocks of LNAs.
- the GapmeRs are preferably 14-16 nucleotides in length and are optionally fully phosphorothioated.
- the DNA gap activates the RNAse H-mediated degradation of targeted RNAs and is also suitable to target transcripts directly in the nucleus.
- Preferred antisense molecules for targeting SIK3 are antisense molecules or constructs having a sequence complementary to a region (such as one described above) of a nucleic acid sequence of an SIK3 mRNA, preferably a sequence complementary to a region of a sequence encoding the amino acid sequence shown in SEQ ID NO: 1 to 4 or in any of SEQ ID NOs 13 to 16, in particular of SEQ ID NOs: 1 or 13, more preferably, a sequence complementary to a region of between about 15 to 25 bp (such as between about 19 and 21 bp) of a sequence encoding the amino acid sequence shown in SEQ ID NO: 1 to 4 or in any of SEQ ID NOs 13 to 16, in particular of SEQ ID NOs: 1 or 13.
- an antisense molecule for targeting SIK3 may be an siRNA selected from the SIK3 siRNA molecules identified as "si”, “s2" "s3, or "s4" herein (eg in Table Al; SEQ ID NOs: 7, 8, 9 and 10, respectively).
- SIK3 Pool As above: sl, s2, s3 and s4 As above N/A
- an antisense molecule for targeting SIK3 may be an shRNA molecule identified as "shSIK3 herein (eg in Table A2; SEQ ID NO: 11).
- the antisense molecules of the invention may be isolated.
- the antisense molecules of the invention may be recombinant, synthetic and/or modified, or in any other way non-natural or not a product of nature.
- a nucleic acid of the invention may contain at least one nucleic acid substitution (or deletion) modification such as between 1 and about 5 such modifications, preferably no more than 1, 2 or 3 such modifications) relative to a product of nature, such as a human nucleic acid.
- the antisense molecules of the invention may be modified by use of non-natural nucleotides, or may be conjugated to another chemical moiety.
- such chemical moieties may be a heterologous nucleic acid conferring increased stability or cell/nucleus penetration or targeting, or may be a non-nucleic acid chemical moiety conferring such properties, of may be a label.
- Certain preferred embodiments pertain to a genetic construct for gene editing that is used as an inhibitor of expression, function and/or stability of SIK3 in the context of the herein described invention.
- genome editing constructs By using genome editing constructs it is possible to modulate the expression, stability and/or activity of SIK3.
- Genome editing approaches are well known in the art and may be easily applied when the respective target genomic sequences are known.
- such approaches may be used in gene therapy using e.g. viral vectors, which specifically target tumour cells in accordance with the above descriptions.
- DNA is inserted, replaced, or removed, from a genome using artificially engineered nucleases, or so called “molecular scissors".
- the nucleases create specific double- stranded break (DSBs) at desired locations in the genome, and harness the cell's endogenous mechanisms to repair the induced break by natural processes of homologous re-combination (HR) and non-homologous end-joining (NHEJ).
- HR homologous re-combination
- NHEJ non-homologous end-joining
- engineered nucleases such as zinc finger nucleases (ZFNs), Transcription Activator- Like Effector Nucleases (TALENs), the CRISPR/Cas system, and engineered meganuclease re-engineered homing endonucleases are routinely used for genome editing.
- ZFNs zinc finger nucleases
- TALENs Transcription Activator- Like Effector Nucleases
- CRISPR/Cas system CRISPR/Cas system
- meganuclease re-engineered homing endonucleases are routinely used for genome editing.
- the rare-cutting endonuclease is Cas9, Cpfl, TALEN, ZFN, or a homing endonuclease may be used.
- DAIS DNA-guided Argonaute interference systems
- said Argonaute (Ago) protein is heterologously expressed from a polynucleotide introduced into said cell in the presence of at least one exogenous oligonucleotide (DNA guide) providing specificity of cleavage to said Ago protein to a preselected locus.
- the TALEN and Cas9 systems are respectively described in WO 2013/176915 and WO 2014/191128.
- the Zinc-finger nucleases (ZFNs) are initially described in Kim, YG; Cha, J.; Chandrasegaran, S. ("Hybrid restriction enzymes: zinc finger fusions to Fok I cleavage domain" (1996). Proc Natl Acad Sci USA 93 (3): 1156-60).
- Cpfl is class 2 CRISPR Cas System described by Zhang et al. (Cpfl is a single RNA-guided Endonuclease of a Class 2 CRIPR-Cas System (2015) Cell; 163:759-771).
- the argonaute (AGO) gene family was initially described in Guo S, Kemphues KJ. ("par-1, a gene required for establishing polarity in C. elegans embryos, encodes a putative Ser/Thr kinase that is asymmetrically distributed" (1995) Cell;81(4):611-20).
- the use of the CRISPR/Cas9, CRISPR/Cpfl or the Argonaute genome-editing systems is particularly adapted to be used in combination with the transfection of guide RNA or guide DNA sequences.
- the guide- RNAs and a nucleic acid sequence coding for Cas9 nickase (or similar enzymes) is transfected into a target cell (preferably a tumour cell) so that they form a complex able to induce a nick event in double-stranded nucleic acid targets in order to cleave the genetic sequence between said nucleic acid targets.
- RNA-nanoparticle formulations it may be useful to deliver the guide RNA-nanoparticle formulations separately from the Cas9.
- a dual-delivery system is provided such that the Cas9 may be delivered via a vector and the guide RNA is provided in a nanoparticie formulation, where vectors are considered in the broadest sense simply as any means of delivery, rather than specifically viral vectors.
- Separate delivery of the guide RNA- nanoparticle formulation and the Cas9 may be sequential, for example, first Cas9 vector is delivered via a vector system followed by delivery of sgRNA-nanoparticle formulation) or the sgRNA-nanoparticle formulation and Cas9 may be delivered substantially contemporaneously (i.e., co-delivery).
- Sequential delivery may be done at separate points in time, separated by days, weeks or even months.
- multiple guide RNAs formulated in one or more delivery vehicles e.g., where some guide RNAs are provided in a vector and others are formulated in nanoparticles
- the Cas9 is also delivered in a nanoparticie formulation.
- the guide RNA-nanoparticle formulation and the Cas9 nanoparticie formulation may be delivered separately or may be delivered substantially contemporaneously (i.e., co- delivery).
- the gene target of such genome-editing approaches may be the gene of SIK3.
- the gene target of such editing may be another gene that controls the expression, function and/or stability of SIK3, for example LKB1 or the glucagon receptor.
- the compounds for genome editing approaches according to the invention comprise at least the use of a guide RNA or DNA complementary to a region (such as one described above) of a SIK3 sequence.
- the compounds for use in genome editing approaches of the invention may include donor sequences homologous to such a region of SIK3, as templates for homology directed repair.
- the donor sequences comprise a mutated sequence of SIK3 that when used in the CRISPR induced repair mechanism in a target cell, is by homologous recombination inserted/copied into the SIK3 genomic locus, and therefore yields into a mutated SIK3 gene which is characterised by a reduced expression, function and/or stability of the expressed SIK3.
- CRISPR/Cas9 genome editing in cancer therapy is reviewed for ex-ample in Khan FA et al: "CRISPR/Cas9 therapeutics: a cure for cancer and other genetic diseases.” (Oncotarget. 2016 May 26. doi: 10.18632/oncotarget.9646; incorporated by reference in its entirety).
- inhibitors of SIK3 may be a hetero-bi-functional compound that contains two ligands connected by a linker, wherein one ligand binds to the target protein (in this case, SIK3 or a gene that controls the expression, amount, function, activity and/or stability of SIK3) and the other ligand binds to and/or recruits a component of the cellular protein degradation machinery such as binding to a ubiquitin ligase protein (eg E3 ubiquitin ligase) or such as recruiting a chaperone protein.
- a ubiquitin ligase protein eg E3 ubiquitin ligase
- hetero-bi-functional compounds examples include PROTACs ("PROteolysis TAgeting Chimera) or HyT ("hydrophobic tagging") molecules, in each case designed to bind to the target protein for the present invention.
- PROTACs and HyT molecules are reviewed in Huang & Dixit 2016 (Cell Research 26:484) and exemplified specifically in, for example, WO 2016/146985A1.
- a PROTAC that binds to the target protein (eg SIK3) with one ligand and with the other ligand to an E3 ubiquitin ligase protein thereby brings the ligase and the target into close proximity. Without being bound by any particular theory it is generally understood that it is this close proximity which in turn triggers the poly-ubiquitination and subsequent proteasome-dependent degradation of the target protein of interest.
- hydrophobic tagging is similar to that of PROTAC, but instead of using a ligand to recruit a specific E3 ligase, a synthetic hydrophobic group, such as adamantane, linked to a chemical moiety that specifically recognizes the target protein (eg SIK3), assumes the role of "recruiter" for the degradation machinery.
- the hydrophobic tag Upon binding to the target protein, the hydrophobic tag mimics or induces a misfolded state.
- modification of the target protein with a bulky hydrophobic side- group attracts the chaperone machinery, the primary goal of which is to help refold misfolded proteins. Since the covalent modification cannot be easily removed, the target protein remains unfolded and is eventually cleared by ubiquitin-proteasome mediated degradation.
- the ligand contained therein that binds to the target protein may be a peptide that binds (preferably, specifically) to such target protein; and in alterative embodiments the ligand that binds to the target protein (eg SIK3) may be a small molecule such as small molecule SIK3 inhibitor that binds (preferably, specifically) to such target protein.
- Exemplary small molecule SIK3 inhibitors are described elsewhere herein, and as well as such small molecule SIK3 inhibitors having utility as inhibitors per-se (that is, not contained in a hetero-bi-functional compound, may - in certain embodiments - be comprised in a hetero-bi-functional compound.
- the SIK3 inhibitor may be a small molecule (in particular, a small molecule ligand or a small cell-permeable molecule).
- a small molecule SIK3 inhibitor can bind to: (i) SIK3 and inhibit the function or activity of SIK3 (eg phosphorylated SIK3); or (ii) a gene (such as LKBl or the glucagon receptor) that controls the expression, amount function, activity and/or stability of SIK3 and, example, thereby modulates the expression, amount, function, activity and/or stability of SIK3 (eg phosphorylated SIK3).
- SIK3 eg phosphorylated SIK3
- a gene such as LKBl or the glucagon receptor
- An inhibitor of SIK3 that is a small molecule can be, for example, any chemical structure or compound (molecule) having a SIK3 inhibitory activity as described herein and a molecular weight of, for example, less than 3000 dalton (Da), preferably less than 1500 Da, most preferably less than 1000 Da
- a small molecule is a compound having a molecular mass of less than about 750 Da, such as less than about 650 or 600 Da, (and in certain embodiments, a small molecule may be less than about 550 or 500 Da).
- the small molecule can have, in certain embodiments: (i) no more than 5 hydrogen bond donors (the total number of nitrogen-hydrogen and oxygen-hydrogen bonds); (ii) no more than 10 hydrogen bond acceptors (all nitrogen or oxygen atoms); and/or (iii) an octanol-water partition coefficient log P not greater than 5.
- the SIK3 inhibitor can be a cell-permeable small organic molecule, such as one that binds to and inhibits the function or activity of SIK3 (in particular, of phosphorylated SIK3).
- the SIK3 inhibitor is dasatinib.
- Dasatinib (or BMS-354825) is a cancer drug produced by Bristol-Myers Squibb and sold under the trade name SPRYCEL.
- the chemical name for dasatinib is N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-l- piperazinyl]-2-methyl-4- pyrimidinyl]amino]-5-thiazolecarboxamide, especially the monohydrate form thereof.
- the molecular formula of dasatinib (monohydrate) is C22H26CIN 7 02S»H 2 0, which corresponds to a formula weight of 506.02 (monohydrate), and dasatinib (monohydrate) has the following chemical structure:
- the SIK3 inhibitor is not dasatinib.
- the SIK3 inhibitor is a variant of dasatinib.
- a "variant" in the context of a small molecule means another small molecule that has a different chemical structure to the reference small molecule (ie, the variant is a different small molecule), wherein the different chemical structure retains one more structural features of the core structure of the reference small molecule.
- the chemical structure of a variant may differ from that of the reference small molecule by the addition, removal or substitution of at least one atom, or addition, modification, removal or substitution of at least one atomic or group substituent, or a change of at least one chemical bond between atoms, compared to the reference small molecule.
- two, three, four, five, or more than five such atomic or group substituents may be added, removed or substituted on the chemical structure of the reference small molecule to provide such a variant of the reference small molecule (eg of dasatinib).
- the invention in particular includes those embodiments where the SIK3 inhibitor a variant of dasatinib.
- the SIK3 inhibitor is the monohydrate of the cyclic compound of claim 3 of EP 1 169 038 B9, or is a salt (or is a solvate, salt, complex, polymorph, crystalline form, racemic mixture, diastereomer, enantiomer, tautomer, isotopically labelled form, prodrug, and combination) thereof.
- the SIK3 inhibitor is (eg a variant of dasatinib being) a cyclic compound of "formula I" or “formula II” as defined on pages 3 to 13 of WO 00/62778A1 (herein, formula I and formula II W0 , respectively), in particular the "Preferred Compounds” thereof as defined on pages 13 and 14 of WO 00/62778A1, and salts thereof.
- the compound is not dasatinib (or is not a monohydrate or salt of dasatinib), such as the compound is not the cyclic compound of claim 3 of EP 1 169 038 B9, or a salt thereof (or not a solvate, salt, complex, polymorph, crystalline form, racemic mixture, diastereomer, enantiomer, tautomer, isotopically labelled form, prodrug, and combination thereof).
- Such disclosures of WO 00/62778A1 are incorporated, solely for such specific purpose by reference herein.
- the SIK3 inhibitor is a cyclic compound of the following formula I (eg a variant of dasatinib) and salts, prodrugs, solvates and stereoisomers (or solvates, salts, complexes, stereoisomers, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, isotopically labelled forms, prodrugs, and combinations thereof) thereof:
- R 6 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, heterocycio, or heterocycloalkyl, each of which is unsubstituted or substituted with Z l7 Z 2 and one or more (preferably, one or two) groups Z 3 ;
- R 2 and R 3 are each independently:
- (1) are each independently hydrogen or R 6 ;
- (1) are each independently hydrogen or R 6 ;
- R 7 , and Rs may together be alkylene, alkenylene or heteroalkyl, completing a 3- to 8-membered saturated or unsaturated ring with the nitrogen atom to which they are attached, which ring is unsubstituted or substituted with Z l7 Z 2 and Z 3 ; or
- any two of R 9 , Rio and Rn may together be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with Z l7 Z 2 and Z 3 ;
- Z 6 is (i) alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, alkylaryl, cycloalkylaryl, heterocycio, or heterocycloalkyl; (ii) a group (i) which is itself substituted by one or more of the same or different groups (i); or (iii) a group (i) or (ii) which is substituted by one or more of the following groups (2) to (16) of the definition of Z l7 Z 2 and
- any two of Z l7 Z 2 , and Z 3 may together be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached; or
- any two of Z l7 Z 2 , and Z 3 may together be -(CH 2 ) r -0- ,where r is 1 to 5, completing a 4- to 8- membered saturated or unsaturated ring together with the atoms to which they are attached;
- Z 4 and Z 5 are each independently:
- (1) are each independently hydrogen or Z 6 ;
- Z 7 and Z 8 , or Z 6 and Z 10 may together be alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached, which ring is unsubstituted or substituted with Z l7 Z 2 and Z 3 ; or
- Z 7 or Z 8 together with Z 9 , may be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with Z l7 Z 2 and Z 3 ;
- Z n and Z 12 are each independently:
- n 1 or 2
- A is selected from carbon and nitrogen
- B is selected from nitrogen, oxygen and sulphur
- X 3 is oxygen or sulphur
- Ri / R2 / R3 / R4 and R 5 are as described above.
- alk or "alkyl” refer to straight or branched chain hydrocarbon groups having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms.
- lower alkyl refers to alkyl groups of 1 to 4 carbon atoms.
- alkenyl refers to straight or branched chain hydrocarbon groups of 2 to 10, preferably 2 to 4, carbon atoms having at least one double bond. Where an alkenyl group is bonded to a nitrogen atom, it is preferred that such group not be bonded directly through a carbon bearing a double bond.
- alkynyl refers to straight or branched chain hydrocarbon groups of 2 to 10, preferably 2 to 4, carbon atoms having at least one triple bond. Where an alkynyl group is bonded to a nitrogen atom, it is preferred that such group not be bonded directly through a carbon bearing a triple bond.
- alkylene refers to a straight chain bridge of 1 to 5 carbon atoms connected by single bonds (e.g., -(CH 2 ) X - wherein x is 1 to 5), which may be substituted with 1 to 3 lower alkyl groups.
- alkenylene refers to a straight chain bridge of 2 to 5 carbon atoms having one or two double bonds that is connected by single bonds and may be substituted with 1 to 3 lower alkyl groups.
- alkynylene refers to a straight chain bridge of 2 to 5 carbon atoms that has a triple bond therein, is connected by single bonds, and may be substituted with 1 to 3 lower alkyl groups.
- aromatic cyclic groups for example 6 membered monocyclic, 10 membered bicyclic or 14 membered tricyclic ring systems
- exemplary aryl groups include phenyl, naphthyl, biphenyl and anthracene.
- cycloalkyl and “cycloalkenyl” refer to cyclic hydrocarbon groups of 3 to 12 carbon atoms.
- halogen and halo refer to fluorine, chlorine, bromine and iodine.
- heterocycle refers to fully saturated or unsaturated, including aromatic (i.e. "heteroaryl") cyclic groups, for example, 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring systems, which have at least one heteroatom in at least one carbon atom- containing ring.
- Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulphur atoms, where the nitrogen and sulphur heteroatoms may optionally be oxidised and the nitrogen heteroatoms may optionally be quaternised.
- the heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system.
- Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2- oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridinyl, pyrazinyl, pyrimidinyl,
- bicyclic heterocyclic groups include indolyl, benzothiazolyl, benzoxazolyl, benzodioxolyl, benzothienyl, quinuclidinyl, quinolinyl, tetra-hydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as f u ro[2,3-c] pyridi nyl, furo[3,2-b]pyridinyl] or furo[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro
- Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl and the like.
- heteroaryl refers to aromatic heterocyclic groups.
- heteroaryl groups include pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furyl, thienyl, oxadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazolyl, triazinyl, and the like.
- salts may in some cases form salts.
- Reference to a compound of the formula I herein is understood to include reference to salts thereof, unless otherwise indicated.
- Salts of the compounds of the formula I may be formed, for example, by reacting a compound I with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilisation.
- Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid, for example, trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, acetates
- Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as benzathines, dicyclohexylamines, hydrabamines, N-methyl-D-glucamines, N-methyl-D-glucamides, t-butyl amines, and salts with amino acids such as arginine, lysine and the like.
- organic bases for example, organic amines
- organic bases for example, organic amines
- benzathines dicyclohexylamines, hydrabamines, N-methyl-D-glucamines, N-methyl-D-glucamides, t-butyl amines
- salts with amino acids such as arginine, lysine and the like.
- the basic nitrogen-containing groups may be quaternised with agents such as lower alkyl halides (e.g. methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others.
- lower alkyl halides e.g. methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
- dialkyl sulfates e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates
- Prodrugs and solvates of compounds of formula I are also contemplated herein.
- the term "Prodrug”, as employed in this context, denotes a compound which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of formula I, or a salt and/or solvate thereof.
- Solvates of the compounds of formula I are preferably hydrates.
- All stereoisomers of the present compounds are contemplated within the scope of this invention.
- Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers.
- the chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations.
- the SIK3 inhibitor is a compound of formula I (eg a variant of dasatinib) where R2 of formula I or formula II W0 is hydrogen, and R3 of formula I or formula II W0 is Rx, wherein Rx has the following formula X:
- Z2 is -Z 4 -NZ 7 Z 8 , -Z 4 -N(Z9)-Z5-NZ 7 Z8 or Z4-N(Z 10 )-Z 5 -H (where Z 4 and Z 5 to Z 10 are as defined herein or in WO 00/62778A1, in particular where Z4 is a single bond); and/or
- Z2 in formula X is a substituent selected from the group consisting of:
- Zl is (preferably) methyl
- Z3 is hydrogen
- Z2 is (preferably) a substituent selected from the group consisting of:
- Z2 may not be:
- the SIK3 inhibitor is a compound of formula I (eg a variant of dasatinib) where R2 of formula I or formula II W0 is hydrogen, and R3 of formula I or formula II W0 is Rdas, wherein Rdas has the following formula Y:
- R6 is aryl, aralkyl, heterocyclo, or heterocycloalkyl (preferably aryl or heteroaryl), each of which is unsubstituted or substituted with Zl, Z2 and one or more (preferably, one or two) groups Z3 (where Zl, Z2 and Z3 are as defined herein or in WO 00/62778A1).
- R6 is a monocyclic aryl or heteroaryl (in particular, a 6 membered monocyclic aryl or heteroaryl, preferably a 6 membered heteroaryl) substituted with one, two or three Zx (in particular with at least one, or two, at an ortho-position on the monocyclic aryl or heteroaryl), where each Zx may be, independently: (i) Zy, where Zy is a Cl-5 (in particular, a CI, C2 or C3) alkyl, alkenyl or alkynyl; (ii) -OH or -OZy; (iii) -SH or -SZy; (iv) halo; or (v) -S02-Zy or -S02-N-(Zy)(Zy).
- Zx may be, independently: (i) Zy, where Zy is a Cl-5 (in particular, a CI, C2 or C3) alkyl, alkenyl or alkynyl
- Zx may be a non-polar substituent.
- the monocyclic aryl or heteroaryl R 6 (when R 5 of formula II W0 is R 6/ ) is, preferably, phenyl or pyridinyl (eg, a pyridin-2-yl, or more preferably pyridin-3-yl), optionally substituted with one, two or three (preferably two) Zx, in particular where one Zx is substituted at the ortho position of the phenyl or pyridinyl, and/or in particular where each Zx is independently selected from the group consiting of: - CI, -F, -Br, -Me, -OMe, -OEt and -CN (preferably, selected from -CI, -F, -Me and -Br).
- a substituted phenyl or pyridinyl such Re, where at least one (or both) of the meta positions is not hydrogen (such as is a Zx as
- the SIK3 inhibitor may be (eg, a variant of dasatinib being) a cyclic compound of any one of claims 1 to 21 of WO 00/62778A1, and salts (or solvates, salts, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, isotopically labelled forms, prodrugs, and combinations) thereof.
- R2, R3, XI, X2, R4, R5 and/or R6 are as defined herein.
- the variant of dasatinib is selected from the group of cyclic compounds consisting of claim 22 of WO 00/62778A1, and salts thereof.
- Such disclosures of WO 00/62778A1 are incorporated by reference herein, solely for such specific purpose.
- the SIK3 inhibitor may be (eg, a variant of dasatinib being) a compound of "formula III" as defined in claim 23 of WO 00/62778A1, in particular is a compound as set forth in claim 23 or 53 of WO 00/62778A1 and salts thereof.
- WO 00/62778A1 is incorporated by reference herein, solely for such specific purpose.
- R2, R3, R4, R5 and/or R6 are as defined above, and/or X3 is (preferably) oxygen.
- the SIK3 inhibitor may be (eg, a variant of dasatinib being) a compound as set forth in claim 59 of WO 00/62778A1 and salts thereof.
- WO 00/62778A1 is incorporated by reference herein, solely for such specific purpose.
- R2, R3, R4, R5 and/or R6 are as defined above, and/or X3 is (preferably) oxygen.
- the SIK3 inhibitor may be (eg, a variant of dasatinib being) a cyclic compound of "formula II" of claim 1 of EP 1169038B9 (formula II EP herein), and salts thereof.
- a variant of dasatinib being a cyclic compound of "formula II" of claim 1 of EP 1169038B9 (formula II EP herein), and salts thereof.
- a SIK3 inhibitor may be a compound (eg a variant of dasatinib) where within formula I being a cyclic compound of the following formula II EP or a salt thereof:
- X 3 is oxygen or sulphur
- R 5 is an aryl group which is substituted with one or more groups selected from alkyl and halo;
- R 6 is: aryl or heteroaryl which is substituted with Z l7 Z 2 and one or more groups Z 3 , wherein
- said aryl is substituted with at least one group Z 3 where Z 3 is -Z 4 -NZ 7 Z 8 where Z 4 is a bond, Z 7 is hydrogen or alkyl, and Z 8 is heterocyclo-substituted alkyl; or
- said heteroaryl is substituted with at least one group Z 3 where Z 3 is -Z 4 -NZ 7 Z 8 where Z 4 is a bond,
- Z 7 is hydrogen or alkyl, and Z 8 is heterocyclo-substituted alkyl; or
- Z 6 is (i) alkyl, alkenyl, alkynyl, cycloalkyl, cyctoalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, alkylaryl, cycloalkylaryl, heterocyclo, or heterocycloalkyl; (ii) a group
- any two of Z l7 Z 2 , and Z 3 may together be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached; or
- any two of Z l7 Z 2 , and Z 3 may together be -0-(CH 2 ) r -0-, where r is 1 to 5, completing a 4- to 8- membered saturated or unsaturated ring together with the atoms to which they are attached;
- Z 4 and Z 5 are each independently:
- (1) are each independently hydrogen or Z 6 ;
- Z 7 and Z 8 , or Z 6 and Z 10 may together be alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached, which ring is unsubstituted or substituted with Z l7 Z 2 and Z 3 ; or
- Z 7 or Z 8 together with Z 9 , may be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with Z l7 Z 2 and Z 3 ;
- Z n and Z 12 are each independently:
- R6 of formula II EP may be Rdas and/or X3 is (preferably) oxygen and/or R5 of formula II EP may be R6 as defined herein.
- the SIK3 inhibitor may be (eg, a variant of dasatinib being) a compound is selected from the group of cyclic compounds consisting of claim 2 of EP 1169038B9, and salts thereof. Such disclosure is incorporated by reference herein solely for such specific purpose.
- the invention also relates to a variant of dasatinib of any of the general (or specific) formula or structures disclosed herein (eg, of formula I, II W0 or II EP ), and salts (or solvates, salts, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, isotopically labelled forms, prodrugs, and combinations) thereof.
- the SIK3 inhibitor can be a variant of dasatinib (that is not dasatinib); ie, that in such embodiments the SIK3 inhibitor is one having the general formula I (or II W0 or II EP ), with the proviso that the SIK3 inhibitor is not compound A8.
- SIK3 inhibitors formula I, II W0 or II EP may be synthesised following the disclosure, in particular Schemes A to XI (and/or the procedures in Examples 1 to 580), of WO 00/62778A1. Such disclosure is incorporated by reference herein solely for such specific purpose.
- SIK3 inhibitors that are a variant of dasatinib may be synthesised according to the procedures described in Example 10 herein.
- the SIK3 inhibitor is, and in a certain aspect the invention relates to, a (cyclic) compound as set forth in Table A3 or Table A4 (in particular, compound B3, B2 or A6), and solvates, salts, stereoisomers, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, isotopically labelled forms, prodrugs, and combinations thereof.
- a (cyclic) compound as set forth in Table A3 or Table A4 in particular, compound B3, B2 or A6
- the SIK3 inhibitor is, and in a certain aspect the invention relates to, a compound as set forth in Table A3 or Table A4, and solvates, salts, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, isotopically labelled forms, prodrugs, and combinations thereof, with one or more (preferably all) of the provisos that the SIK3 inhibitor or the compound is not compound A9, B8 and/or B9.
- the SIK3 inhibitor is, and in a certain aspect the invention relates to, a compound of any of the general (or specific) formula or structures disclosed herein (eg, of formula I, II W o), and salts (or solvates, salts, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, isotopically labelled forms, prodrugs, and combinations) thereof, with one or more (preferably all) of the proviso that when, in general formula II W0 , X3 is oxygen, n is 1, Rl is hydrogen, R2 is hydrogen, R3 is Rdas and one of R4 or R5 is hydrogen, then the other of R4 or R5 is an R6 that is (i) not 2-chloro-6-ethoxyphenyl; and/or (ii) not 3-chloro-4- fluorophenyl.
- the general formula II W0 , X3 is oxygen
- n is 1
- Rl is hydrogen
- the SIK3 inhibitor is, and in a certain aspect the invention relates to, a compound of any of the general (or specific) formula or structures disclosed herein (eg, of formula I, II W o), and salts (or solvates, salts, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, isotopically labelled forms, prodrugs, and combinations) thereof, with one or more (preferably all) of the proviso that when, in general formula II W0 , n is 1, A is nitrogen, B is sulphur, X 3 is oxygen, Ri is hydrogen, R 2 is hydrogen, R4 is hydrogen, R 3 is formula Y and R 5 is Re, then R 6 is not 2-chloro-6-methylphenyl.
- the SIK3 inhibitor is, and in a certain aspect the invention relates to, a compound of any of the general (or specific) formula or structures disclosed herein (eg, of formula I, II W o) / and salts (or solvates, salts, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, isotopically labelled forms, prodrugs, and combinations) thereof, with one or more (preferably all) of the proviso that when, in general formula II W0 , n is 1, A is nitrogen, B is sulphur, X 3 is oxygen, Ri is hydrogen, R 2 is hydrogen, R4 is hydrogen, R 5 is R 6 and R 6 is:
- a phenyl substituted at an ortho position with a -CI then either (x) the other ortho position is hydrogen, or a Zx (as defined above) that is not methyl (such as, a Zx that is -CI, -F, -Br, -OMe, -
- a phenyl substituted at an ortho position with a methyl then either (x) the other ortho position is hydrogen, or a Zx (as defined above) that is not -CI (such as, a Zx that is -F, -Br, -Me, -OMe, -OEt or -CN), and preferably at least one of the meta or the para positions is substituted with Zx as defined above; or (y) the other ortho is -CI and at least two of the meta or para positions are substituted with Zx (as defined above); or (z) R3 is not Rdas.
- a Zx as defined above
- the invention also relates to a method for the treatment or prevention of a disease, disorder or condition (such as a proliferative disorder eg cancer or a tumour) in a subject (such as one in need thereof), comprising administering to said subject at least once an effective amount of (i) a variant of dasatinib of any of the general (or specific) formula or structures disclosed herein (formula I, II W0 or II EP ), or (ii) a compound as set forth in Table A3 or Table A4 (in particular, compound is B3, B2 or A6), or a salt (or a solvate, salts, complex, polymorph, crystalline form, racemic mixture, diastereomer, enantiomer, tautomer, isotopically labelled form, prodrug, and combination) of (i) or (ii), or comprising administering to said subject at least once an effective amount of the pharmaceutical composition as described above.
- a disease, disorder or condition such as a proliferative disorder eg cancer
- the invention also relates to (i) a variant of dasatinib of any of the general (or specific) formula or structures disclosed herein (formula I, II W0 or II EP ), or (ii) a compound as set forth in Table A3 or Table A4, or a salt (or a solvates salt, complex, polymorph, crystalline form, racemic mixture, diastereomer, enantiomer, tautomer, isotopically labelled form, prodrug, and combination) of (i) or (ii), for use in medicine, such as in the treatment or the prevention of a disease, disorder or condition (such as a proliferative disorder eg cancer or a tumour) in a subject (such as one in need thereof).
- a disease, disorder or condition such as a proliferative disorder eg cancer or a tumour
- the compound is B3, B2 or A6.
- the compound has formula IIwo / n is 1, A is nitrogen, B is sulphur, X 3 is oxygen, is hydrogen, R 2 is hydrogen, R4 is hydrogen, R 5 is Re and e is a monocyclic heteroaryl substituted with one, two or three Zx, with at least one Zx at an ortho-position on the monocyclic aryl or heteroaryl; wherein each Zx may be, independently: (i) Zy, where Zy is a CI, C2 or C3 alkyl, alkenyl or alkynyl; (ii) -OH or -OZy; (iii) -SH or -SZy; (iv) halo; or (v) -S02-Zy or -S02-N-(Zy)(Zy).
- the SIK3 inhibitor is bosutinib.
- Bosutinib (SKI-606), marketed under the trade name BOSULIF, is a tyrosine kinase inhibitor or use in the treatment of cancer.
- the chemical name for bosutinib (monohydrate) is 3-Quinolinecarbonitrile, 4-[(2,4-dichloro-5- methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl) propoxy]-, hydrate (1: 1). Its chemical formula is C26H29Cl2N 5 0 3 »H 2 0 (monohydrate); its molecular weight is 548.46 (monohydrate), equivalent to 530.46 (anhydrous).
- Bosutinib (monohydrate) has the following chemical structure:
- the SIK3 inhibitor is not bosutinib.
- the SIK3 inhibitor is a variant of bosutinib, in particular, a compound claim of any one of claims 1 to 20, or defined in any one of claims 21 to 29 of US 6,002,008, the disclosure of which is hereby incorporated by reference herein, solely for such specific purpose.
- SIK-selective inhibitors have been described by others, in particular for use in distinct indications (for example, for treating inflammatory and/or immune disorders such as inflammatory bowel disease and graft-versus-host disease (for example, WO 2013/136070A1, WO 2014/093383A1, WO 2014/140313A1 and WO 2016/023014A2,).
- the SIK3 inhibitor may be one selected from:
- the SIK3 inhibitor may be a compound within a general formula of I, IA or IB of WO 2014/093383A1, or is as one claimed by any one of claims 1 to 28 or one defined in claim 49 of WO 2014/093383A1, or a pharmaceutically acceptable salt thereof.
- the SIK3 inhibitor may be a compound within a general formula of I, II or III-A of WO 2016/023014A2, or is one defined in any one of claims 1 to 230 of WO 2016/023014A2, or a pharmaceutically acceptable salt thereof.
- such SIK3 inhibitor can be a cell-permeable small molecule that binds to and inhibits the function or activity of SIK3, in particular phosphorylated SIK3.
- the SIK3 inhibitor may be formulated into a pharmaceutical composition appropriate to facilitate administration to animals or humans.
- composition means a mixture of substances.
- pharmaceutical composition means a mixture of substances including a therapeutically active substance (such as a SIK3 inhibitor) for pharmaceutical use.
- a pharmaceutical composition comprising a SIK3 inhibitor (of, or for use with the invention), and a pharmaceutically acceptable excipient, stabiliser or carrier.
- the pharmaceutical composition comprises a SIK3 inhibitor of Table A3 or Table A4.
- the invention also relates to a pharmaceutical composition including:
- the pharmaceutical composition of the invention may comprise between 0.1% and 100% (w/w) active ingredient (for example, a SIK3 inhibitor), such as about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 8% 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98% or 99%, preferably between about 1% and about 20%, between about 10% and 50% or between about 40% and 90%.
- active ingredient for example, a SIK3 inhibitor
- compositions are intended to include any and all solvents, solubilisers, fillers, stabilisers, binders, absorbents, bases, buffering agents, lubricants, controlled release vehicles, diluents, emulsifying agents, humectants, dispersion media, coatings, antibacterial or antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration.
- solvents solubilisers, fillers, stabilisers, binders, absorbents, bases, buffering agents, lubricants, controlled release vehicles, diluents, emulsifying agents, humectants, dispersion media, coatings, antibacterial or antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration.
- diluents emulsifying agents
- humectants humectants
- dispersion media coatings, antibacterial or antifungal agents, isotonic and absorption
- the pharmaceutical composition of (or for use with) the invention is, typically, formulated to be compatible with its intended route of administration.
- routes of administration include oral, parenteral, e.g., intrathecal, intra-arterial, intravenous, intradermal, subcutaneous, oral, transdermal (topical) and transmucosal administration.
- Solutions or suspensions used for parenteral, intradermal, or subcutaneous application, as well as comprising a compound of (or for use with) the invention can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine; propylene glycol or other synthetic solvents; anti-bacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfate; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
- the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
- compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
- suitable carriers include physiological saline, bacteriostatic water, Kolliphor® EL (formerly Cremophor ELTM; BASF, Parsippany, N.J.) or phosphate buffered saline (PBS).
- the injectable composition should, typically, be sterile and be fluid to the extent that easy syringability exists. It should, typically, be stable under the conditions of manufacture and storage and be preserved against the contaminating action of microorganisms such as bacteria and fungi.
- the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheylene glycol, and the like), and suitable mixtures thereof.
- the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the requited particle size in the case of dispersion and by the use of surfactants.
- Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
- isotonic agents for example, sugars, polyalcohols such as manitol, sorbitol, and sodium chloride in the composition.
- Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.
- Sterile injectable solutions can be prepared by incorporating the compound of (or for use with) the invention (e.g., a SIK3 inhibitor) in the required amount in an appropriate solvent with one or a combination of ingredients described herein, as required, followed by filtered sterilisation.
- dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those described herein.
- the preferred methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
- Oral compositions as well as comprising a compound of (or for use with) the invention (eg a SIK3 inhibitor), generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
- the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Stertes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavouring agent such as peppermint, methyl salicylate, or orange flavouring.
- a binder such as microcrystalline cellulose, gum tragacanth or gelatin
- an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch
- a lubricant such as magnesium stearate or Stertes
- a glidant such as colloidal silicon dioxide
- a rectal composition can be any rectally acceptable dosage form including, but not limited to, cream, gel, emulsion, enema, suspension, suppository, and tablet.
- One preferred dosage form is a suppository having a shape and size designed for introduction into the rectal orifice of the human body.
- a suppository usually softens, melts, or dissolves at body temperature.
- Suppository excipients include, but are not limited to, theobroma oil (cocoa butter), glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol.
- the compounds of (or for use with) the invention eg a SIK3 inhibitor
- Cells such as immune cells (eg CAR T cells) for use with the invention can be included in pharmaceutical formulations suitable for administration into the bloodstream or for administration directly into tissues or organs.
- a suitable format is determined by the skilled person (such as a medical practitioner) for each patient, tissue, and organ, according to standard procedures.
- Suitable pharmaceutically acceptable carriers and their formulation are known in the art (see, e.g. Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed., 1980).
- Such cells when formed in a pharmaceutical composition, are preferably formulated in solution at a pH from about 6.5 to about 8.5.
- Excipients to bring the solution to isotonicity can also be added, for example, 4.5% mannitol or 0.9% sodium chloride, pH buffered with art-known buffer solutions, such as sodium phosphate.
- Other pharmaceutically acceptable agents can also be used to bring the solution to isotonicity, including, but not limited to, dextrose, boric acid, sodium tartrate, propylene glycol, polyols (such as mannitol and sorbitol) or other inorganic or organic solutes.
- a media formulation is tailored to preserve the cells while maintaining cell health and identity.
- a premixture including an aqueous solution of anticoagulant (ACD-A), an equal amount of dextrose (50%), and phosphate buffered saline (PBS), or the like is pre-mixed and aliquoted in a volume to typically match or approximate the cellular matrix or environment from which the cell was extracted from the tissue or organ.
- ACD-A anticoagulant
- dextrose 50%
- PBS phosphate buffered saline
- Systemic administration can also be by transmucosal or transdermal means.
- penetrants appropriate to the barrier to be permeated are used in the formulation.
- penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives.
- Transmucosal administration can be accomplished through the use of nasal sprays or suppositories.
- the pharmaceutical compositions can be formulated into ointments, salves, gels, or creams as generally known in the art.
- the pharmaceutical composition is formulated for sustained or controlled release of a compound of (or for use with) the invention (eg a SIK3 inhibitor).
- a compound of (or for use with) the invention eg a SIK3 inhibitor.
- Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art.
- the materials can also be obtained commercially (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art.
- Dosage unit form as used herein includes physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
- the specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals.
- the pharmaceutical composition comprising a SIK3 inhibitor is in unit dose form of between 10 and 1000 mg SIK3 inhibitor. In some embodiments, the pharmaceutical composition comprising an SIK3 inhibitor is in unit dose form of between 10 and 200 mg SIK3 inhibitor. In some embodiments, the pharmaceutical composition comprising an ABP is in unit dose form of between 200 and 400 mg SIK3 inhibitor. In some embodiments, the pharmaceutical composition comprising an SIK3 inhibitor is in unit dose form of between 400 and 600 mg SIK3 inhibitor. In some embodiments, the pharmaceutical composition comprising an SIK3 inhibitor is in unit dose form of between 600 and 800 mg SIK3 inhibitor. In some embodiments, the pharmaceutical composition comprising an SIK3 inhibitor is in unit dose form of between 800 and 1000 mg SIK3 inhibitor.
- kits are provided for producing a single-dose administration unit.
- the kit can contain both a first container having a dried active ingredient and a second container having an aqueous formulation.
- the kit can contain single and multi-chambered pre-loaded syringes.
- Toxicity and therapeutic efficacy (eg effectiveness) of such active ingredients can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, eg, for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population).
- the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50/ED50.
- Active agents which exhibit large therapeutic indices are preferred. While compounds that exhibit toxic side effects may be used, care should be taken to design a delivery system that targets such compounds to the site of affected tissue in order to minimise potential damage to uninfected cells and, thereby, reduce side effects.
- the data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage of the active ingredients (eg a SIK3 inhibitor or TNF, variant of TNF or an agonist of TNFR1 or TNFR2), such as for use in humans.
- the dosage of such active ingredients lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity.
- the dosage may vary within this range depending upon the dosage form employed and the route of administration utilised.
- the (therapeutically) effective dose can be estimated initially from cell culture assays.
- a dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (ie, the concentration of the active ingredients which achieves a half-maximal inhibition of symptoms) as determined in cell culture. Such information can be used to more accurately determine useful (eg effective) amounts or doses, such as for administration to humans.
- the pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.
- an effective amount of the SIK3 inhibitor or the pharmaceutical composition can be one that will elicit the biological, physiological, pharmacological, therapeutic or medical response of a cell, tissue, system, body, animal, individual, patient or human that is being sought by the researcher, scientist, pharmacologist, pharmacist, veterinarian, medical doctor, or other clinician, eg, lessening of the effects/symptoms of a disorder, disease or condition, such as a proliferative disorder, for example, a cancer or tumour, or killing or inhibiting growth of a cell involved with a proliferative disorder, such as a tumour cell.
- the effective amount can be determined by standard procedures, including those described below.
- the effective amount administered at least once to a subject in need of treatment with a SIK3 inhibitor is, typically, between about 0.01 mg/kg and about 100 mg/kg per administration, such as between about 1 mg/kg and about 10 mg/kg per administration.
- the effective amount administered at least once to said subject of a SIK3 inhibitor is between about 0.01 mg/kg and about 0.1 mg/kg per administration, between about 0.1 mg/kg and about 1 mg/kg per administration, between about 1 mg/kg and about 5 mg/kg per administration, between about 5 mg/kg and about 10 mg/kg per administration, between about 10 mg/kg and about 50 mg/kg per administration, or between about 50 mg/kg and about 100 mg/kg per administration.
- the appropriate dosage of a SIK3 inhibitor (or a pharmaceutical composition comprised thereof) will depend on the type of disease to be treated, the severity and course of the disease, whether the SIK3 inhibitor and/or pharmaceutical composition is administered for preventive or therapeutic purposes, previous therapy, the patient's clinical history, age, size/weight and response to the SIK3 inhibitor and/or pharmaceutical composition, and the discretion of the attending physician.
- the SIK3 inhibitor and/or pharmaceutical composition is suitably administered to the patient at one time or over a series of treatments.
- the total number of administrations for a given course of treatment may consist of a total of about 2, 3, 4, 5, 6, 7, 8, 9, 10 or more than about 10 treatments.
- a treatment may be given once every day (or 2, 3 or 4 times a day) for a week, a month or even several months.
- the course of treatment may continue indefinitely.
- the amount of the SIK3 inhibitor and/or pharmaceutical composition administered will depend on variables such as the type and extent of disease or indication to be treated, the overall health, age, size/weight of the patient, the in vivo potency of the SIK3 inhibitor and/or pharmaceutical composition, and the route of administration.
- the initial dosage can be increased beyond the upper level in order to rapidly achieve the desired blood-level or tissue level. Alternatively, the initial dosage can be smaller than the optimum, and the daily dosage may be progressively increased during the course of treatment.
- Human dosage can be optimised, e.g., in a conventional Phase I dose escalation study designed to run from relatively low initial doses, for example from about 0.01 mg/kg to about 20 mg/kg of active ingredient.
- Dosing frequency can vary, depending on factors such as route of administration, dosage amount and the disease being treated. Exemplary dosing frequencies are once per day, once per week and once every two weeks.
- Formulation of an SIK3 inhibitor of (or for use with) the present is within the ordinary skill in the art. In some embodiments of the invention such SIK3 inhibitor is lyophilised and reconstituted in buffered saline at the time of administration.
- the SIK3 inhibitor and/or pharmaceutical composition of may further result in a reduced relapsing of the disease to be treated or reduce the incidence of drug resistance or increase the time until drug resistance is developing; and in the case of cancer may result in an increase in the period of progression-free survival and/or overall survival.
- the invention is based on the surprising finding that SIK3 is associated with resistance against anti-tumour immune responses, and the inventors herein describe various aspects related to the treatment of proliferative disorders (eg cancers or tumours), in particular by overcoming the resistance of cells involved with the proliferative disorder to a cell-mediated immune response.
- proliferative disorders eg cancers or tumours
- a disorder treatable by the subject matter of the invention is preferably one characterised by a resistance of one or more cells involved in (eg affected by) the disorder (such as the proliferative disorder) against a defence response of the host organism, such as resistance that is associated with a pathological phenotype.
- a resistance of such cells eg cells of a tumour or cancer
- one or more immune responses in particular a cell-mediated immune response, mounted by the subject/ patient suffering from the disorder.
- the term "resistance” refers to an acquired or natural resistance of a cell involved with (eg of or affected by) a proliferative disease, such as tumour or cancer cell, to a patient's own immune response (such as a cell- mediated immune response, including TNF), or to immune responses aided by immune therapy/immunotherapy such as adoptive T-cell transfer or treatment with checkpoint blockers. Therefore, a resistant cell (eg a resistant tumour or cancer cell) is more likely to escape and survive humoural and/or cellular immune defence mechanisms in a subject having the disorder (such as the tumour or cancer).
- a treatment of a resistant proliferative disease, such as tumour/cancer resistance, in context of the invention shall be effective if, compared to a non-treated control, the cell involved with the proliferative disease (such as a cell of the tumour of cancer) becomes more sensitive or susceptible to an immune response (such as a cell-mediated immune response or TNF) - in other words will be more likely to be recognised and/or neutralised (for example by cytotoxic processes such as apoptosis) by the subject's immune response.
- an immune response such as a cell-mediated immune response or TNF
- cell(s) involved with the proliferative disorder may be resistant against (to) a cell-mediated immune response; and/or such cell(s) may have or display a resistant phenotype.
- the terms "cellular resistance”, “cell resistance” and the like refers to a resistance of the subject cell(s) (such as a tumour or cancer cell) to a cell-mediated immune response, such as a cytotoxic T lymphocyte (CTL) response or TNF exposure (eg, the tumour or tumour cell being nonresponsive to, or having reduced or limited response to a CTL targeting a tumour cell or to exposure the TNF).
- CTL cytotoxic T lymphocyte
- TNF eg, the tumour or tumour cell being nonresponsive to, or having reduced or limited response to a CTL targeting a tumour cell or to exposure the TNF.
- a tumour cell may show a reduced or limited response when contacted with a CTL specific for an antigen expressed on that tumour cell or when contacted with TNF.
- a reduced or limited response is a reduction to a 90% cytotoxic T cell or TNF response, preferably a reduction to 80%, 70%, 60%, 50% or more preferably a reduction to 40%, 30%, 20% or even less. In this case, 100% would denote the state wherein the CTLs or TNF can kill all of the subject cells involved with the proliferative disorder in a sample.
- a subject cell eg a tumour cell
- a patient's (cell-mediated or TNF) immune response may be tested in-vitro by contacting a sample of the subjects such cells (eg autologous tumour cells) with (eg autologous) T-cells or (eg recombinant) TNF and thereafter quantifying the survival/proliferation rate of the (eg) tumour cells.
- the reduction in (cell-mediated) immune response is determined by comparing cancer samples of the same cancer before and after the resistance is acquired (for example induced by therapy), or by comparing with a cancer sample derived from a different cancer which is known to have no resistance to the CTL or to TNF.
- the treatments of the present invention include the sensitisation of cells involved with the proliferative disorder against CTL and/or TNF and therefor to decrease resistance of such cells.
- a decrease of (eg tumour) cell resistance against CTL and/or TNF is preferably a significant increase of CTL or TNF-mediated toxicity, preferably a 10% increase, more preferably 20%, 30%, 40%, 50%, 60%, 70%, 80% or more, even more preferably 2 fold increase, 3 fold, 4 fold, 5 fold or more.
- a resistant phenotype of the cells involved with the proliferative disorder is displayed by such cells when a subject suffering from the proliferative disorder (eg a cancer or tumour) has been previously treated with an (immune)therapy and, for example, such proliferative disorders has progressed despite such prior (immune)therapy.
- the subject may be distinguished (characterised) as having been previously treated with an immunotherapy and whose tumour has progressed, in particular whose tumour relapsed, recurred or did not respond.
- a class of subject suitable for the various therapeutic methods of the invention can be those whose tumour (or cancer) has progressed (such as has relapsed or recurred, or has not responded to) after prior treatment with a cancer immunotherapy.
- the prior immunotherapy comprised administration of an immune checkpoint inhibitor, such as a prior immunotherapy comprising (administration of) an antibody binding to an immune checkpoint molecule, a non-antibody peptide or a small molecule (in each case, such as described elsewhere).
- such prior treatment may be any immunotherapy as described elsewhere herein, including adoptive immune cell transfer (eg TCR or CAR T cell therapy), an anti-tumour vaccine, an antibody binding to an immune checkpoint molecule (such as CTLA-4, PD-1 or PD-L1), or a non-antibody peptide or small molecule ligand of an immune (inhibitory) checkpoint molecule (in each case, such as described elsewhere.
- Other immunotherapy (such as may be a a prior treatment of a subject) may include: (x) administration of a drug that activates STING protein, which may lead to stimulation of the innate immune system of the subject.
- Drugs that agonise STING can include cyclic dinucleotides (CDNs), such as compounds Aduro Biotech's ADU-S100, an analogue of 2'3'-cGAMP (Fu et al, 2015; Sci Transl Med 7; 283:ra52); (y) administration of A2aR antagonists such as SCH58261, SYN115, ZM241365 or FSPTP (as reviewed by Leone et al, 2015; Comp Struct Biotech J 13:265); and/or (z) targeting IDOl/TDO and their downstream effectors, such as administration of indoleamine-2,3-dioxygenase which is in clinical trials with the aim at reverting cancer-induced immunosuppression (as reviewed by Platten et al, 2015; Front Immun 5:673).
- CDNs cyclic dinucleotides
- the subject may suffer from a tumour or cancer, and such cancer may have progressed (such as has relapsed or recurred, or has not responded to) after prior radiotherapy. Accordingly, in other embodiments, the subject may be distinguished (characterised) as having a tumour that progressed, in particular relapsed, recurred or did not respond to, prior radiotherapy.
- the invention also includes those embodiments where cells involved with the proliferative disorder have been subjected to prior immunotherapy.
- the subject may have received (eg treatment by) prior immunotherapy (eg one described elsewhere herein), such as by administration with (a ligand to) an immune checkpoint molecule (eg administration of an immune checkpoint inhibitor), and/or any other prior immunotherapy such as described elsewhere herein.
- the subject may be distinguished (characterised) as having been previously treated with an anti-TNF agent for an autoimmune disorder (eg rheumatoid arthritis).
- an anti-TNF agent for an autoimmune disorder eg rheumatoid arthritis
- the subject may be suffering from a malignancy that had arisen during (eg as a consequence) of such treatment with an anti-TNF agent.
- the subject may suffer from a haematological malignancy that had arisen during (eg as a consequence of) such treatment with an anti-TNF agent, such as a subject suffering from an iatrogenic immunodeficiency- associated lymphoproliferative disease.
- a disorder treatable by the subject matter of the invention is, in certain embodiments, one characterised by expression of SIK3; in particular, one characterised by such expression that is aberrant, for example over- (or under-) expression or representation or activity of SIK3 (in particular of phosphorylated SIK3) in a given cell or tissue (such as those cells or tissues involved with the proliferative disease of the subject) compared to that in a healthy subject or a normal cell.
- the invention includes those embodiments wherein cells involved with the proliferative disorder (eg cells of the tumour) are characterised by expression and/or activity of SIK3 (in particular, such cells express mRNA and/or protein of SIK3, and/or are positive for such SIK3 expression and/or activity).
- the subject is distinguished (eg, can be characterised) - such as being suitable for the treatment methods of the present invention, by having cells involved with the proliferative disorder characterised by expression and/or activity of SIK3, in particular such cells express mRNA and/or protein of SIK3, and/or are positive for such SIK3 expression and/or activity.
- a disorder treatable by the subject matter of the invention may, in other certain embodiments, be one characterised by (such as a disorder that is further characterised by) one or more applicable biomarkers.
- appcable biomarker means any one (or more) of the genes (as well as SIK3) expressed by the cell involved with the proliferative disorder that the inventors have surprisingly found are involved in the SIK3- mediated cellular resistance against an immune response (eg a cell-mediated immune response such as TNF).
- Such genes include (as well as SIK3, in particular phosphorylated SIK3):
- TNFR1 (or TNFR2), such as the presence of (or an amount of) or expression and/or activity of TNFR1 (or TNFR2), i n pa rticu la r TNFR1;
- LKB1 such as the presence of (or an amount of) or expression and/or activity of LKB1, in particular increased amount or activity of LKB1 or pLKBl;
- HDACs one or more class II (eg Ila) HDACs, eg HDAC4, such as the presence of (or an amount of) or expression and/or activity of such HDAC, in particular increased amount or activity of such HDAC or pHDAC, especially in the cytoplasm of cells of the tumour;
- NF-kappa-B such as the presence of (or an amount of) or expression and/or activity of NF-kappa-B, in particular increased amount or activity of NF-kappa-B or acetylated NF-kappa-B, especially in the nucleus of cells of the tumour; and/or (f) one or more anti-apoptotic genes, such as the presence of (or an amount of) or expression and/or activity of one or more anti-apoptotic genes, in particular one or more of such genes under transcriptional control by NF-kappa-B.
- the proliferative disorder may be a tumour selected from the group consisting of: head and neck cancer, squamous cell carcinoma, multiple myeloma, solitary plasmacytoma, renal cell cancer, retinoblastoma, germ cell tumours, hepatoblastoma, hepatocellular carcinoma, melanoma, rhabdoid tumour of the kidney, Ewing Sarcoma, chondrosarcoma, any haemotological malignancy (e.g., chronic lymphoblastic leukemia, chronic myelomonocytic leukemia, acute lymphoblastic leukemia, acute lymphocytic leukemia, acute myelogenous leukemia, acute myeloblasts leukemia, chronic myeloblastic leukemia, Hodgekin's disease, non- Hodgekin's lymphoma, chronic lymphocytic leukemia, chronic myelogenous leukemia, myelogenous leukemia, myelogenous le
- the proliferative disorder may be a tumour selected from the group consisting of: pancreatic cancer, breast cancer, melanoma, ovarian cancer, oesophageal cancer, sarcomoa and colorectal cancer; or the cells involved with the proliferative disorder are those of or derived from one of such tumours.
- administration of, exposure to or cell contact with the SIK3 inhibitor, when in a subject may be associated with one or more of:
- an increase in the ratio of anti-tumour and tumour-suppressive immune cells eg, the ratio of CD8 T cells/Tregs or the ratio of Teff/MDSC;
- IDO indoleamine-pyrrole 2,3-dioxygenase
- administration of, exposure to or cell contact with the SIK3 inhibitor, when in a subject may enhance a cell-mediated immune response in the subject; in particular wherein said enhancement is associated with one or more of the features (a) to (f) as set forth above.
- administration of, exposure to or cell contact with the SIK3 inhibitor, when in a subject may not be associated with one or more of: • an increase in the production of one or more anti-inflammatory cytokines, in particular IL-10; and/or
- SIK3 can be used for diagnostic purposes to detect, diagnose, or monitor diseases and/or conditions associated with cellular resistance against a cell-mediated immune response; and in particular aberrant and/or localised expression/activity of SIK3 (in particular phosphorylated SIK3) can be so used.
- the diseases, disorders or conditions is a cancer or tumour (such as a solid tumour), including one or more of those described elsewhere herein; more preferably one or more of the disorders described elsewhere herein, such as pancreatic cancer, breast cancer, melanoma, ovarian cancer, oesophageal cancer, sarcomoa and colorectal cancer.
- the use of one or more other certain genes is envisioned in a method for determining whether a subject, such as a mammalian subject (eg a human), has a phenotype, or is at risk of developing a phenotype, that is associated with (eg a disease, disorder or condition, in particular a proliferative disorder such as a cancer or tumour, including a solid tumour, associated with) cellular resistance against a cell-mediated immune response and/or that is associated with (aberrant) expression or activity of SIK3 (eg SIK3 of a cell involved with the proliferative disorder), the method comprising the step of:
- an applicable biomarker eg protein or mRNA of
- an applicable biomarker as described above, such as SIK3 and/or HDAC4
- a biological sample from said subject such as the applicable biomarker of the cancer or tumour cell
- the detection of the applicable biomarker in (eg cancer or tumour cells of) the sample indicates a/the phenotype (or a/the risk of developing a phenotype) that is associated with cellular resistance against the cell- mediated immune response, and/or that is associated with (aberrant) expression or activity of SIK3, in the subject.
- the detection of the applicable biomarker may comprise determining the presence or an amount of SIK3 (and in particular phosphorylated SIK3), or activity thereof, in the sample, in particular such SIK3 associated with or of tumour cells of the subject.
- the detection of the applicable biomarker may comprise determining the presence or an amount of one or more of the other applicable biomarkers as described above.
- the in invention relates to a method for determining the presence or an amount of SIK3 (and in particular phosphorylated SIK3) in a biological sample from a subject, the method comprising the steps of:
- a biological sample will (preferably) comprise cells or tissue of the subject, or an extract of such cells or tissue, in particular where such cells are those (usually, typically; or in the case or a specific subject as suspected to be) involved with the proliferative disorder (eg tumour cells such as cells of a solid tumour).
- the tumour or cell thereof may be one or, or derived from, one of the tumours described elsewhere herein.
- the method will also comprise a step of:
- such detection and/or determination methods can be practiced as a method of diagnosis, such as a method of diagnosis whether a mammalian subject (such as a human subject or patient) has a disease, disorder or condition, in particular (the presence of) a proliferative disorder such as a cancer or tumour (or has a risk of developing such a disease, disorder or condition) that is associated with cellular resistance against a cell-mediated immune response and/or that is associated with (aberrant) expression or activity of SIK3; in particular a (solid) tumour, such as one having cellular resistance against a cell-mediated immune response.
- a mammalian subject such as a human subject or patient
- a disease, disorder or condition in particular (the presence of) a proliferative disorder such as a cancer or tumour (or has a risk of developing such a disease, disorder or condition) that is associated with cellular resistance against a cell-mediated immune response and/or that is associated with (aberrant) expression or activity of SIK3; in particular a (
- the cellular resistance against a cell-mediated immune response is cellular resistance against a T cell-mediated immune response, in particular cellular resistance to the killing effect of TNF and/or of TNFR1 or TNFR2 signalling.
- particular embodiments of these detection and/or diagnostic methods may also comprise a step of determining the presence or amount of TNF in the sample, wherein the presence of (or an amount of) TNF in the sample indicates a/the phenotype (or a/the risk of developing a phenotype) that is associated with cellular resistance against the cell-mediated immune response, and/or associated with (aberrant) expression or activity of SIK3, in the subject.
- amount of TNF in the sample is determined qualitatively.
- the subject is distinguished as having: (i) a plasma concentration of TNF greater than about 2 pg/mL or 5 pg/mL in a plasma sample from the subject; and/or (ii) an intratumoural concentration of TNF greater than about 0.5 pg/mL or 1 pg/mL plasma from a tissue sample from the subject, indicates the (presence of the) phenotype (or the proliferative disorder or a risk of developing the proliferative disorder) that is associated with cellular resistance against the cell-mediated immune response, and/or associated with expression or activity of SIK3, in the subject.
- TNF-alpha Immunoassay Methodologies to determine the presence or amount of TNF in a sample are described elsewhere herein (in particular, quantitative detection of TNF using ELISA assays such as a Quantitkine TNF-alpha Immunoassay; as are amounts of TNF that, if are exceeded by the TNF present in the sample, indicate that a phenotype associated with cellular resistance against the cell-mediated immune response, and/or associated with (aberrant) expression or activity of SIK3, in the subject.
- the biological sample is one obtained from a mammalian subject like a human patient.
- the term "biological sample” is used in its broadest sense and can refer to a bodily sample obtained from the subject (eg, a human patient).
- the biological sample can include a clinical sample, i.e., a sample derived from a subject.
- samples can include, but are not limited to: peripheral bodily fluids, which may or may not contain cells, e.g., blood, urine, plasma, mucous, bile pancreatic juice, supernatant fluid, and serum; tissue or fine needle biopsy samples; tumour biopsy samples or sections (or cells thereof), and archival samples with known diagnosis, treatment and/or outcome history.
- Bio samples may also include sections of tissues, such as frozen sections taken for histological purposes.
- the term "biological sample” can also encompass any material derived by processing the sample. Derived materials can include, but are not limited to, cells (or their progeny) isolated from the biological sample, nucleic acids and/or proteins extracted from the sample. Processing of the biological sample may involve one or more of, filtration, distillation, extraction, amplification, concentration, fixation, inactivation of interfering components, addition of reagents, and the like.
- these detection, determination and/or diagnostic methods may be a computer- implemented method, or one that is assisted or supported by a computer.
- information reflecting the presence or an amount of the applicable biomarker (eg SIK3) to be determined (or activity thereof) in a sample is obtained by at least one processor, and/or information reflecting the presence or an amount of such marker (or activity thereof) in a sample is provided in user readable format by another processor.
- the one or more processors may be coupled to random access memory operating under control of or in conjunction with a computer operating system.
- the processors may be included in one or more servers, clusters, or other computers or hardware resources, or may be implemented using cloud-based resources.
- the operating system may be, for example, a distribution of the LinuxTM operating system, the UnixTM operating system, or other open-source or proprietary operating system or platform.
- Processors may communicate with data storage devices, such as a database stored on a hard drive or drive array, to access or store program instructions other data.
- Processors may further communicate via a network interface, which in turn may communicate via the one or more networks, such as the Internet or other public or private networks, such that a query or other request may be received from a client, or other device or service.
- the computer-implemented method of detecting the presence or an amount of the applicable biomarker (or activity thereof) in a sample is provided as a kit.
- Such detection, determination and/or diagnosis methods can be conducted as an in-vitro (eg ex-vivo) method, and can be, for example, practiced using the kit of the present invention (or components thereof).
- An in- vitro method may use, involve or be practised on immortalised cell lines (such as those replicated, cultured or indefinitely maintained outside of the body of an animal or human), or it may be use, involve or be practised in-vitro using cells (such as primary cells) directly or freshly obtained from the body of an animal of human (eg, practised as a so-called "ex-vivo" method).
- the biological sample is a tissue sample from the subject, such as a sample of a tumour or a cancer from the subject.
- tissue sample may be a biopsy sample of the tumour or a cancer such as a needle biopsy sample, or a tumour biopsy section or an archival sample thereof.
- tissue sample may comprise living, dead or fixed cells, such as from the tumour or a cancer, and such cells may be suspected of expressing (e.g. aberrantly or localised) the applicable biomarker to be determined.
- determination and/or diagnosis method of the invention can comprise, such as in a further step, comparing the detected amount (or activity of) of (eg protein or mRNA of) the applicable biomarker (eg SIK3, and in particular phosphorylated SIK3) with a standard or cut-off value; wherein a detected amount greater than the standard or cut-off value indicates a phenotype (or a risk of developing a phenotype) that is associated with cellular resistance against the cell-mediated immune response in the subject and/or is associated with is associated with (aberrant) expression or activity of SIK3 in the subject.
- the applicable biomarker eg SIK3, and in particular phosphorylated SIK3
- Such a standard or cut-off value may be determined from the use of a control assay, or may be pre-determined from one or more values obtained from a study or a plurality of samples having known phenotypes.
- a cut-off value for a diagnostic test may be determined by the analysis of samples taken from patients in the context of a controlled clinical study, and determination of a cut-off depending on the desired (or obtained) sensitivity and/or specificity of the test.
- Examples of methods useful in the detection of include immunoassays, such as the enzyme linked immunosorbent assay (ELISA) and the radioimmunoassay (RIA), which employ an antigen binding protein ("ABP") such as an antibody or an antigen-binding fragment thereof, that specifically binds to such applicable biomarker.
- immunoassays such as the enzyme linked immunosorbent assay (ELISA) and the radioimmunoassay (RIA), which employ an antigen binding protein (“ABP”) such as an antibody or an antigen-binding fragment thereof, that specifically binds to such applicable biomarker.
- ELISA enzyme linked immunosorbent assay
- RIA radioimmunoassay
- an "antigen binding protein” as used herein includes the meaning of a protein that specifically binds one or more epitope(s) displayed by or present on a target antigen.
- an antigen binding protein is an antibody (or a fragment thereof), however other forms of antigen binding protein are also envisioned by the invention.
- the ABP may be another (non-antibody) receptor protein derived from small and robust non- immunoglobulin "scaffolds"; such as those equipped with binding functions for example by using methods of combinatorial protein design (Gebauer & Skerra, 2009; Curr Opin Chem Biol, 13:245).
- non-antibody ABPs include: Affibody molecules based on the Z domain of Protein A (Nygren, 2008; FEBS J 275:2668); Affilins based on gamma-B crystalline and/or ubiquitin (Ebersbach et al, 2007; J Mo Biol, 372:172); Affimers based on cystatin (Johnson et al, 2012; Anal Chem 84:6553); Affitins based on Sac7d from Sulfolobus acidcaldarius (Krehenbrink et al, 2008; J Mol Biol 383:1058); Alphabodies based on a triple helix coiled coil (Desmet et al, 2014; Nature Comms 5:5237); Anticalins based on lipocalins (Skerra, 2008; FEBS J 275:2677); Avimers based on A domains of various membrane receptors (Silverman et a
- An antigen binding protein is "specific" when it binds to one antigen (such as the applicable biomarker, eg SIK3, and in particular phosphorylated SIK3) more preferentially (eg, more strongly or more extensively) than it binds to a second antigen.
- one antigen such as the applicable biomarker, eg SIK3, and in particular phosphorylated SIK3
- the term “specifically binds” (or “binds specifically” and the like) used herein in the context of an ABP means that said ABP will preferentially bind to the applicable biomarker to be determined than to bind to other proteins (or other molecules), such as preferentially binding to such SIK3 compared to one or more of SIK2 and/or SIK1 and/or other kinase.
- the binding affinity of the ABP to the one antigen is at least 2-fold, 5-fold, at least 10-fold, at least 20-fold, at least 50-fold, at least 100-fold, at least 200-fold, at least 500-fold, at least 1000-fold, at least 2000-fold, at least 5000-fold, at least 10000-fold, at least 10 5 -fold or even at least 10 6 -fold, most preferably at least 2-fold, compared to its affinity to the other targets (e.g. paralogues of SIK3, such as SIK2 and/or SIK1).
- the other targets e.g. paralogues of SIK3, such as SIK2 and/or SIK1
- the antigen binding protein binds to phosphorylated SIK3 preferentially to binding to un-phosphorylated SIK3.
- the term "antibody” may be understood in the broadest sense as any immunoglobulin (Ig) that enables binding to its epitope.
- An antibody as such is a species of an ABP.
- Full length "antibodies” or “immunoglobulins” are generally heterotetrameric glycoproteins of about 150 kDa, composed of two identical light and two identical heavy chains. Each light chain is linked to a heavy chain by one covalent disulphide bond, while the number of disulphide linkages varies between the heavy chain of different immunoglobulin isotypes. Each heavy and light chain also has regularly spaced intrachain disulphide bridges. Each heavy chain has an amino terminal variable domain (VH) followed by three carboxy terminal constant domains (CH).
- VH amino terminal variable domain
- CH carboxy terminal constant domains
- Each light chain has a variable N-terminal domain (VL) and a single C-terminal constant domain (CL).
- VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR).
- CDR complementarity determining regions
- FR framework regions
- Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
- the variable regions of the heavy and light chains contain a binding domain that interacts with an antigen.
- the constant regions of the antibodies may mediate the binding of the immunoglobulin to cells or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system.
- Other forms of antibodies include heavy-chain antibodies, being those which consist only of two heavy chains and lack the two light chains usually found in antibodies.
- Heavy-chain antibodies include the hcIgG (IgG-like) antibodies of camelids such as dromedaries, camels, llamas and alpacas, and the IgNAR antibodies of cartilaginous fishes (for example sharks).
- Single-domain antibodies include single-domain antibodies (sdAb, called Nanobody by Ablynx, the developer) being an antibody fragment consisting of a single monomeric variable antibody domain.
- Single-domain antibodies are typically produced from heavy-chain antibodies, but may also be derived from conventional antibodies.
- An antibody may, in certain embodiments be a polyclonal antibody, and in other embodiments may be a monoclonal antibody.
- polyclonal antibody refers to a mixture of antibodies which are genetically different since produced by plasma cells derived from multiple somatic recombination and clonal selection events and which, typically, recognise a different epitope of the same antigen.
- the term "monoclonal antibody” or "mAb” as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies based on their amino acid sequence. Monoclonal antibodies are typically highly specific. Furthermore, in contrast to conventional (polyclonal) antibody preparations which typically include different antibodies directed against different determinants (e.g. epitopes) of an antigen, each mAb is typically directed against a single determinant on the antigen. In addition to their specificity, mAbs are advantageous in that they can be synthesised by cell culture (hybridomas, recombinant cells or the like) uncontaminated by other immunoglobulins. The mAbs herein include for example chimeric, humanised or human antibodies or antibody fragments.
- chimeric antibody refers to an antibody whose light and/or heavy chain genes have been constructed, typically by genetic engineering, from immunoglobulin variable and constant regions which are identical to, or homologous to, corresponding sequences of different species, such as mouse and human.
- heavy chain genes derive from a particular antibody class or subclass while the remainder of the chain derives from another antibody class or subclass of the same or a different species. It covers also fragments of such antibodies.
- a typical therapeutic chimeric antibody is a hybrid protein composed of the variable or antigen-binding domain from a mouse antibody and the constant or effector domain from a human antibody, although other mammalian species may be used.
- humanised antibody refers to specific chimeric antibodies, immunoglobulin chains or fragments thereof (such as Fab, Fab', F(ab') 2 , Fv, or other antigen-binding sub-sequences of antibodies), which contain minimal sequence (but typically, still at least a portion) derived from non-human immunoglobulin.
- humanised antibodies are human immunoglobulins (the recipient antibody) in which CDR residues of the recipient antibody are replaced by CDR residues from a non-human species immunoglobulin (the donor antibody) such as a mouse, rat or rabbit having the desired specificity, affinity and capacity.
- the framework sequence of said antibody or fragment thereof may be a human consensus framework sequence.
- Fv framework residues of the human immunoglobulin need to be replaced by the corresponding non-human residues to increase specificity or affinity.
- humanised antibodies can comprise residues which are found neither in the recipient antibody nor in the imported CDR or framework sequences. These modifications are made to further refine and maximise antibody performance.
- the humanised antibody will comprise substantially all of at least one, and typically at least two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the framework regions are those of a human immunoglobulin consensus sequence.
- the humanised antibody optimally also will comprise at least a portion of an immunoglobulin constant region, typically that of a human immunoglobulin.
- Antibody fragments include "Fab fragments", which are composed of one constant and one variable domain of each of the heavy and the light chains, held together by the adjacent constant region of the light chain and the first constant domain (CHI) of the heavy chain. These may be formed by protease digestion, e.g. with papain, from conventional antibodies, but similar Fab fragments may also be produced by genetic engineering. Fab fragments include "Fab-SH", which are Fab fragments containing at least one free sulfhydryl group.
- Fab' fragments differ from Fab fragments in that they contain additional residues at the carboxy terminus of the first constant domain of the heavy chain including one or more cysteines from the antibody hinge region.
- Fab' fragments include "Fab'-SH", which are Fab' fragments containing at least one free sulfhydryl group.
- antibody fragments include F(ab') 2 fragments, which contain two light chains and two heavy chains containing a portion of the constant region between the CHI and CH2 domains, such that an interchain disulphide bond is formed between the two heavy chains.
- a F(ab') 2 fragment thus is composed of two Fab' fragments that are held together by a disulphide bond between the two heavy chains.
- F(ab') 2 fragments may be prepared from conventional antibodies by proteolytic cleavage with an enzyme that cleaves below the hinge region, e.g. with pepsin, or by genetic engineering.
- An "Fv region” comprises the variable regions from both the heavy and light chains, but lacks the constant regions.
- Single-chain antibodies” or “scFv” are Fv molecules in which the heavy and light chain variable regions have been connected by a flexible linker to form a single polypeptide chain, which forms an antigen binding region.
- An "Fc region” comprises two heavy chain fragments comprising the CH2 and CH3 domains of an antibody.
- the two heavy chain fragments are held together by two or more disulphide bonds and by hydrophobic interactions of the CH3 domains.
- the presence of the applicable biomarker may be detected by detection of the presence of mRNA that encodes such applicable biomarker, or fragments of such mRNA.
- Methods to detect the presence of such mRNA (or fragments) can include, PCR (such as quantitative RT- PCR), hybridisation (such as to Illumina chips), nucleic-acid sequencing etc.
- PCR such as quantitative RT- PCR
- hybridisation such as to Illumina chips
- nucleic-acid sequencing can involve or comprise steps using one or more nucleic acids as described herein, such as PCR primers or PCR probes, or hybridisation probes, that bind (eg specifically) to such mRNA.
- the ABP or nucleic acid typically, will be labelled with a detectable labelling group.
- labelling groups fall into a variety of classes, depending on the assay in which they are to be detected: a) isotopic labels, which may be radioactive or heavy isotopes; b) magnetic labels (e.g., magnetic particles); c) redox active moieties; d) optical dyes; enzymatic groups (e.g.
- a secondary reporter e.g., leucine zipper pair sequences, binding sites for secondary antibodies, metal binding domains, epitope tags, etc.
- Suitable labelling groups include, but are not limited to, the following: radioisotopes or radionuclides (e.g., 3 H, 14 C, 15 N, 35 S, 90 Y, 99 Tc, lu ln, 125 l, 131 l), fluorescent groups (e.g., FITC, rhodamine, lanthanide phosphors), enzymatic groups (e.g., horseradish peroxidase, beta-galactosidase, luciferase, alkaline phosphatase), chemiluminescent groups, biotinyl groups, or predetermined polypeptide epitopes recognised by a secondary reporter (eg, leucine zipper pair sequences, binding sites for secondary antibodies, metal binding domains, epitope tags).
- radioisotopes or radionuclides e.g., 3 H, 14 C, 15 N, 35 S, 90 Y, 99 Tc, lu ln, 125
- the labelling group is coupled to the ABP or nucleic acid via spacer arms of various lengths to reduce potential steric hindrance.
- spacer arms of various lengths to reduce potential steric hindrance.
- Various methods for labelling proteins are known in the art and may be used.
- the ABP or nucleic acid may be labelled with a secondary reporter (e.g., leucine zipper pair sequences, binding sites for secondary antibodies, metal binding domains, epitope tags, etc.).
- the means eg ABP or nucleic acid
- the means for the detection of protein or mRNA of the applicable biomarker (eg SIK3)
- a detectable label eg SIK3
- label or “labelling group” refers to any detectable label, including those described herein.
- the detection/diagnostic methods of the invention involve an immunohistochemistry (IHC) assay or an immunocytochemistry (IC) assay.
- IHC immunohistochemistry
- IC immunocytochemistry
- IHC and ICC are art recognised, and include the meanings of techniques employed to localise antigen expression that are dependent on specific epitope-antibody interactions.
- IHC typically refers to the use of tissue sections
- ICC typically describes the use of cultured cells or cell suspensions.
- positive staining is typically visualised using a molecular label (eg, one which may be fluorescent or chromogenic). Briefly, samples are typically fixed to preserve cellular integrity, and then subjected to incubation with blocking reagents to prevent non-specific binding of the antibodies. Samples are subsequently typically incubated with primary (and sometimes secondary) antibodies, and the signal is visualised for microscopic analysis.
- such embodiments of the detection/diagnostic methods of the invention may include a step of preparing a subject IHC or ICC preparation tissue or cells (such as those present in the biological samples obtained from a subject); and preferably wherein the detection of binding of an ABP to the applicable biomarker (eg SIK3, and in particular phosphorylated SIK3) expressed by the tissues of cells said IHC or ICC preparation indicates: (i) a phenotype (or a risk of developing a phenotype) that is associated with cellular resistance against the cell-mediated immune response in the subject; and/or (ii) said subject has or has a risk of developing disease, condition or disorder that is associated with (aberrant) expression or activity of SIK3.
- an ABP eg SIK3, and in particular phosphorylated SIK3
- an ABP that binds to (preferably specifically to) the applicable biomarker (eg SIK3, and in particular phosphorylated SIK3) and that does not bind (eg does not detectably bind) to a validation IHC or ICC preparation of mammalian tissues or cells other than to (detectably) bind to the applicable biomarker (eg such SIK3), that is expressed by the tissue cells or of said validation IHC or ICC preparation.
- the applicable biomarker eg SIK3, and in particular phosphorylated SIK3
- said validation and/or subject IHC or ICC preparation is one selected from the list consisting of: a frozen section, a paraffin section, and a resin section, in each case of the tissues and/or cells; and/or wherein the tissues and/or cell comprised in either (or both) said IHC or ICC preparations are fixed.
- the tissues and/or cells or such IHC or ICC preparation(s) may be fixed by an alcohol, an aldehyde, a mercurial agent, an oxidising agent or a picrate.
- said validation and/or subject IHC or ICC preparation is a formalin- fixed paraffin embedded (FFPE) section of said tissues and/or cells; and/or wherein said validation and/or subject IHC or ICC preparation is subjected to antigen retrieval (AR).
- AR antigen retrieval
- Such AR may comprise protease-induced epitope retrieval (PIER) or heat-induced epitope retrieval (HIER).
- the ABP used in such methods is, preferably, validated.
- the ABP is validated to (detectably) binds to the applicable biomarker (eg SIK3, and in particular phosphorylated SIK3) expressed by the cells and/or tissues of said validation IHC or ICC preparation, but does not (detectably) bind to a control IHC or ICC preparation of control cells and/or tissues that do not express the applicable biomarker (eg such as SIK3).
- the applicable biomarker eg SIK3, and in particular phosphorylated SIK3
- control cells are gene knock-down or gene knock-out cells and/or tissues for the applicable biomarker (eg SIK3); more preferably, wherein said gene knock-down or gene knock-out cells and/or tissues are siRNA or shRNA gene knockdown or gene knock-out for such applicable biomarker.
- biomarker eg SIK3
- control cells may comprise cells from a cell-line selected from the list consisting of PANCl and said control cells and/or tissues that do not express such applicable biomarker (eg SIK3) comprise cells of said cell line that have been transfected with a SIK3 siRNA or shRNA selected from those of Tables Al and A2; and/or said validation IHC or ICC preparation comprises cells from M579 cells transduced with shSIK3 lentiviral vectors (such as described in Example 8).
- a cell-line selected from the list consisting of PANCl and said control cells and/or tissues that do not express such applicable biomarker (eg SIK3) comprise cells of said cell line that have been transfected with a SIK3 siRNA or shRNA selected from those of Tables Al and A2; and/or said validation IHC or ICC preparation comprises cells from M579 cells transduced with shSIK3 lentiviral vectors (such as described in Example 8).
- the ABP is used with said validation and/or subject IHC or ICC preparation at a working concentration of less than about 50ug/mL, 25ug/mL, 20ug/mL, 15ug/mL, lOug/mL, 7.5ug/mL, 5ug/mL, 2.5ug/mL, lug/mL, 0.5ug/mL, 0.2ug/ml or 0.
- said ABP does not (detectable) bind to said validation immunohistochemistry (IHC) preparation of mammalian cells or tissues other than to (detectably) bind to the applicable biomarker (eg SIK3, and in particular phosphorylated SIK3) expressed by the mammalian cells or tissue of said IHC preparation, in particular at a concentration that is about 2-fold higher than said working concentration, and more particularly at a concentration that is about 5-fold higher than said working concentration
- IHC validation immunohistochemistry
- the ABP used may be a polyclonal antibody; and preferably may be a rabbit antibody.
- the invention relates to a method for determining (or diagnosing) (eg, by in-vitro and/or ex-vivo methods) whether a subject (such as a human subject or patient) has (or has a risk of developing) a disease, disorder or condition that is associated with cellular resistance against a cell-mediated immune response and/or that is associated with (aberrant) expression or activity of SIK3; in particular a proliferative disorder (eg a cancer or tumour), such as one having cellular resistance against a cell-mediated immune response (eg a T cell- mediated immune response); wherein said determination/diagnosis is made with the involvement of a functional assay measuring a biological response, such as one described elsewhere herein.
- a functional assay measuring a biological response
- contacting cells (eg tumour cells) of the subject (eg, cell suspected to be) involved with the disease, disorder or condition with a SIK3 inhibitor in the presence of a cell-mediated immune response such as: (i) (an effective amount of) immune cells selected from the group consisting of: lymphocytes, T-cells, CTLs and
- TILs or (ii) (an effective amount of) a pro-inflammatory cytokine such as TNF;
- an enhancement of the cell-mediated immune response against such cells of the subject indicates that the subject has (or has a risk of developing) such disease, disorder or condition.
- One or more of such steps may be in-vitro steps.
- the invention relates to a method for determining (eg, by in-vitro and/or ex-vivo methods) the resistance of a cell involved with a proliferative disease (eg a cancer or tumour) to a cell-mediated immune response, the method comprising the steps or:
- a cell-mediated immune response such as: (i) immune cells selected from the group consisting of: lymphocytes, T-cells, CTLs and TILs, or (ii) (an effective amount of) a pro-inflammatory cytokine such as TNF; and
- an enhancement of the cell-mediated immune response against such cells indicates that such cells have a resistance to a cell-mediated immune response.
- One or more of such steps may be in-vitro steps.
- the cells involved with a proliferative disorder are provided as a biological sample obtained from a subject (such as a human subject or patient) that has (or has a risk of developing) a disease, disorder or condition that is associated with cellular resistance against a cell-mediated immune response and/or that is associated with (aberrant) expression or activity of SIK3.
- the enhancement of the cell-mediated immune response can be determined by, for example, increased cytotoxicity of the cells of the subject, increased Caspase 8 and/or Caspase 9 cleavage, decreased expression and/or activity of NF-kappa-B (in particular decreased amount or activity of NF-kappa-B or acetylated NF-kappa-B, especially in the nucleus of cells of the tumour) and/or decreased expression and/or activity of one or more anti-apoptotic genes (in particular one or more of such genes under transcriptional control of NF-kappa-B).
- Methods to determine such biological responses are described elsewhere herein, for example including the chromium-release cytotoxicity assay described above.
- the cells of the subject contacted with the cell-mediated immune response are provided (such as by obtaining) a biological sample from the subject, wherein the sample comprises cells of the subject (such as cells of a tumour or cancer of the subject).
- a biological sample from the subject such as cells of a tumour or cancer of the subject.
- Particular embodiments of such method also comprise a step of providing (such as by obtaining) a biological sample from the subject, in particular where such step is conducted prior to the contacting step.
- the detection, a determination and/or diagnostic method may be used as a method for monitoring (or prognosing) the success (or likelihood of success or risk or remission) of treatment of a subject being treated, or intended to be treated, with a treatment method of the invention.
- the sample from the subject is determined to contain the presence of (or an indicative amount of) one or more of the above applicable biomarkers (eg SIK3, and in particular phosphorylated SIK3), and/or the presence of (or an indicative amount of) TNF, then this indicates that (a future) treatment with a method of the invention (eg administration of a SIK3 inhibitor) may be successful, or more likely to be successful, for such subject; and/or (2) if, during the course of such treatment (eg administration of a SIK3 inhibitor), a reduction in (such as Jess than an indicative amount of), or the absence of, one or more of the above applicable biomarkers (eg such SIK3) (or Caspase 8 and/or Caspase 9) or expression (or activity) thereof, is determined in the sample from the subject, then this indicates that such treatment with a method of the invention (eg administration of a SIK3 inhibitor) is or was successful, or is more likely to be successful if continued, for such subject.
- a method of the invention
- the invention relates to a method of diagnosing and treating a disease, disorder or condition characterised by the presence of or an amount of, and/or characterised by (aberrant) expression or activity of, SIK3 (such as a proliferative disorder, eg a tumour or cancer) in a subject, such as a human patient, comprising:
- the invention relates to an ABP binding to (preferably specifically to) protein of the applicable biomarker (eg SIK3, and in particular phosphorylated SIK3, or HDAC4 or phosphorylated HDAC4), or a nucleic acid that can bind to (such as specifically to) mRNA of such applicable biomarker, for use in (eg, in-vitro and/or ex-vivo) diagnosis, such as in the detection of (or determination of the risk of developing) a disease, disorder or condition in a (mammalian) subject, such as a human patient, in particular of a disease, disorder or condition that is associated with cellular resistance against a cell-mediated immune response (such as a proliferative disorder, eg a tumour or cancer), and/or that is associated with (aberrant) expression or activity of SIK3.
- the applicable biomarker eg SIK3, and in particular phosphorylated SIK3, or HDAC4 or phosphorylated HDAC4
- an ABP that is capable of binding to or binds to (eg specifically to) SIK3 (and in particular to phosphorylated SIK3, or HDAC4 or phosphorylated HDAC4) for/in (eg, in-vitro and/or ex-vivo) diagnosis.
- an ABP such as a monoclonal antibody
- SIK3 phosphorylated SIK3
- phosphorylated SIK3 for use in the diagnosis of a disease, disorder or condition in a subject that is associated with cellular resistance against a cell-mediated immune response (such as a cancer), and/or that is associated with (aberrant) expression or activity of SIK3.
- the ABP or nucleic acid for use for such detection may be any as described elsewhere herein.
- kits such as one for performing the diagnostic methods or the determination methods or the detection methods (or the monitoring or prognostic methods) of the invention, eg, for determining the presence, absence, amount, function, activity and/or expression of the applicable biomarker (eg SIK3, and in particular to phosphorylated SIK3, or HDAC4 or phosphorylated HDAC4) in a sample (eg a biological sample), such as on cells in a sample.
- the kit comprises an ABP and/or a nucleic acid as described above and, optionally one or more additional components.
- an additional component may comprise instructions describing how to use the ABP or a nucleic acid or kit, for detecting the presence of the applicable biomarker in the sample, such as by detecting binding between the ABP and protein such applicable biomarker, and/or detecting binding between the nucleic acid and mRNA of such applicable biomarker.
- Such instructions may consist of a printed manual or computer readable memory comprising such instructions, or may comprise instructions as to identify, obtain and/or use one or more other components to be used together with the kit.
- the additional component may comprise one or more other item, component, reagent or other means useful for the use of the kit or practice of a detection method of the invention, including any such item, component, reagent or means disclosed herein useful for such practice.
- the kit may further comprise reaction and/or binding buffers, labels, enzymatic substrates, secondary antibodies and control samples, materials or moieties etc.
- the additional component may comprise means of detecting the presence of protein of the applicable biomarker (eg SIK3, and in particular the phosphorylated SIK3), such as detecting binding between the ABP and such protein.
- the applicable biomarker eg SIK3, and in particular the phosphorylated SIK3
- ABP a substance that can be linked to the ABP and the presence of the ABP can be observed in a variety of ways.
- a method for screening for diseases, disorders or conditions can involve the use of the kit, or simply the use of one of the disclosed ABPs and the determination of the extent to which ABP binds to the protein of the applicable biomarker (eg SIK3, and in particular the phosphorylated SIK3), in a sample.
- the applicable biomarker eg SIK3, and in particular the phosphorylated SIK3
- degree of ABP binding can be used to determine how much of the applicable biomarker (eg such SIK3) is in a sample.
- Subjects or samples with an amount of such applicable biomarker that is greater than a predetermined amount can be characterised as having a disease, disorder or condition mediated by SIK3 (such as one mediated by the (aberrant) expression, function, activity and/or stability of SIK3), in particular SIK in tumour cells.
- the kit further comprises one or more of the following: standards of protein or mRNA of the applicable biomarker (eg SIK3, and in particular phosphorylated SIK3), positive and/or negative controls for ABP or nucleic acid binding, a vessel for collecting a sample, materials for detecting binding of the ABP or nucleic acid to protein or mRNA (as applicable) of the applicable biomarker in said sample, and reagent(s) for performing said detection.
- standards of protein or mRNA of the applicable biomarker eg SIK3, and in particular phosphorylated SIK3
- positive and/or negative controls for ABP or nucleic acid binding e.g SIK3, and in particular phosphorylated SIK3
- positive and/or negative controls for ABP or nucleic acid binding e.g SIK3, and in particular phosphorylated SIK3
- a vessel for collecting a sample
- kits as described above for performing the (eg in vitro) diagnostic or detection methods of the invention are used in a related other aspect the invention related to a kit as described above for use in a (eg in vitro and/or ex-vivo) determination/diagnostic method of the present invention.
- the diagnostic method comprises a step of surgically obtaining a (eg, tissue) sample from the subject;
- the kit comprises: (a) either (x) a nucleic acid capable of binding specifically to an applicable biomarker (as described above, such as SIK3 or HDAC4), or (y) an ABP binding specifically to applicable biomarker (as described above, such as SIK3 or HDAC4); and (b) optionally (i) instructions describing how to use the ABP or a nucleic acid or kit for detecting SIK3 activity in the (tissue) sample; and/or (ii) one or more other item, component, reagent or other means useful for the use of the kit or the detection of SIK3 activity in the (tissue) sample.
- surgically refers to a step that may comprise a significant intervention practiced on the animal or human body, such as taking a biopsy sample, for example a tissue sample of a solid tumour.
- a biopsy sample for example a tissue sample of a solid tumour.
- other less less significant steps may include taking of, or sampling, blood, for exmaple by venous puncture or skin-prick. In certain embodiments, it does not include sampling blood by venous puncture or skin-prick, or other non- (or less-) significant method of diagnosis practiced on the human or animal body.
- kits of the invention may be accompanied by instructions, including those to use them for determining the amount, activity and/or expression of the applicable biomarker (eg SIK3, and in particular phosphorylated SIK3, or HDAC4 or phosphorylated HDAC4), such as in tumour cells in a sample.
- the applicable biomarker eg SIK3, and in particular phosphorylated SIK3, or HDAC4 or phosphorylated HDAC4
- the various determination(screening)/diagnostic aspects of the invention may be used to identify (eg, to distinguish) wherein the disease, disorder or condition is, and/or is determined to be, (or the subject having such disease, disorder or condition is distinguished to be) one suitable for treatment with a SIK3 inhibitor.
- the subject eg, from whom the sample was obtained
- an immunotherapy such as one descirbed elsewhere herein
- the subject had been previously treated with (eg, is distinguished (characterised) as having had) prior radiotherapy, and whose tumour has progressed, in particular whose tumour relapsed, recurred or did not respond.
- the subject eg, from whom the sample was obtained
- had been previously treated with eg, is distinguished (characterised) as having had) prior radiotherapy, and whose tumour has progressed, in particular whose tumour relapsed, recurred or did not respond.
- the subject eg, from whom the sample was obtained
- the subject had been previously treated with, or is being treated with, (eg, is distinguished (characterised) by administration of) an anti-TNF agent for an autoimmune disorder (eg rheumatoid arthritis).
- an anti-TNF agent for an autoimmune disorder eg rheumatoid arthritis
- the subject may suffer from, or may be at increased risk from suffering from, a malignancy arising during (eg as a consequence) of such treatment with an anti-TNF agent.
- the subject may suffer from, or may be at increased risk of suffering from, a haematological malignancy arising during (eg as a consequence of) such treatment with an anti-TNF agent, such as a subject suffering from, or at increased risk of suffering from, an iatrogenic immunodeficiency-associated lymphoproliferative disease.
- a haematological malignancy arising during (eg as a consequence of) such treatment with an anti-TNF agent, such as a subject suffering from, or at increased risk of suffering from, an iatrogenic immunodeficiency-associated lymphoproliferative disease.
- the subject eg, from whom the sample was obtained
- is being considered for treatment with (eg, is distinguished (characterised) by being under consideration for administration of) an anti-TNF agent for an autoimmune disorder (eg rheumatoid arthritis).
- an anti-TNF agent for an autoimmune disorder eg rheumatoid arthritis
- Such an embodiment may be used to determine those subjects suffering from an autoimmune disorder (eg rheumatoid arthritis) who may have an increased risk of developing a malignancy (such as a haematological malignancy eg an iatrogenic immunodeficiency-associated lymphoproliferative disease) during treatment of their autoimmune disease with an anti-TNF agent.
- a malignancy such as a haematological malignancy eg an iatrogenic immunodeficiency-associated lymphoproliferative disease
- a method for identifying (and/or characterising) a compound such as a compound suitable for the treatment of a disease, disorder or condition (such as a proliferative disorder) that is characterised by cellular resistance against a cell-mediated immune response and/or one that is characterised by (aberrant) expression or activity of SIK3, the method comprising the steps of: • bringing into contact a first cell and the candidate compound, wherein the first cell expresses SIK3 (eg, a protein or mRNA of SIK3); and • determining the expression, activity (eg kinase activity), function and/or stability of the (eg protein or mRNA of) SIK3 (in particular, of phosphorylated SIK3), in the first cell,
- SIK3 eg, a protein or mRNA of SIK3
- a reduced expression, activity (eg kinase activity) function and/or stability of the (eg protein or mRNA of) SIK3, in said first cell contacted with the candidate compound compared to said first cell not contacted with said candidate compound indicates that the candidate compound is a compound suitable for the treatment of the disease, disorder or condition.
- a method for identifying (and/or characterising) a compound such as a compound suitable for the treatment of a disease, disorder or condition (such as a proliferative disorder) that is characterised by cellular resistance against a cell-mediated immune response and/or one that is characterised by (aberrant) expression or activity of SIK3, the method comprising the steps of:
- SIK3 eg, a protein or mRNA of SIK3
- an enhanced cytotoxicity of the cell-mediated immune response against the first cell contacted with the candidate compound compared to the cytotoxicity of the cell-mediated immune response against the first cell not contacted with the candidate compound indicates that the candidate compound is a compound suitable for the treatment of the disease, disorder or condition.
- the activity of the (eg protein or mRNA of) SIK3 in the first cell may be determined directly (eg, by antibody detection of SIK3 protein or by PCR of SIK3 mRNA), or may be determined by determining the presence or an amount of phosphorylated HDAC4 in the first cells, in particular in the cytoplasm of the first cell. For example, a reduction in phosphorylated HDAC4 in the cytoplasm of such first cell would indicate reduced activity of SIK3 in such cell.
- the methods also include the step of providing (such as by obtaining) the first cell and/or the candidate compound and/or (components of) the cell-mediated immune response, in particular where each of such steps is conducted prior to the contacting step.
- the methods of such aspects will be in-vitro (or ex-vivo) methods; that is, typically the methods are those not practiced on the body of a human or animal.
- one or more of the steps of such methods may be in-vitro steps.
- methdos are practiced to identify a suitable candidate compound for purposes of further drug development. That is, in typical (but not all) embodiments, such methods are practiced (especially, if an ex-vivo methods) not to determine (eg diagnose) if a compound is a candidate for the treatment of a particular human or animal.
- the reduction (or enhancement) of expression, activity function and/or stability or SIK3 (in particular, of phosphorylated SIK3), or the enhancement (or reduction) in cytotoxicity is, preferably, identified by reference to a control method.
- the control method may be one practiced in the absence of any candidate compound, or with compound having a known effect on such expression, function, activity and/or stability (such as a positive or negative control), and/or one practiced in the absence of (one or more components of) a cell-mediated immune response.
- the (components of) cell-mediated immune response is a second cell which is a cytotoxic immune cell, for example a cytotoxic T-lymphocyte (CTL), capable of immunologically recognising the first cell.
- the containing step of such embodiment comprises bringing into contact a first cell and the candidate compound and a second cell, wherein the first cell expresses SIK3 (eg, a protein or mRNA of SIK3) and the second cell is a cytotoxic immune cell, for example a cytotoxic T-lymphocyte (CTL), capable of immunologically recognising the first cell.
- SIK3 eg, a protein or mRNA of SIK3
- CTL cytotoxic T-lymphocyte
- the (components of) cell-mediated immune response is a cell-free medium that has previously contained immunologically stimulated immune cells, for example cytotoxic T-lymphocytes (CTLs).
- CTLs cytotoxic T-lymphocytes
- Such immune cells may be stimulated by samples of the first cell and/or by polyclonal stimulants such as CD3-CD28 bead stimulation.
- the contacting step of such embodiment comprises bringing into contact a first cell and the candidate compound and a cell-free medium, wherein the first cell expresses SIK3 (eg, a protein or mRNA of SIK3) and the cell-free medium had previously contained immunologically stimulated immune cells, for example a cytotoxic T-lymphocyte (CTL), such as those capable of immunologically recognising the first cell.
- SIK3 eg, a protein or mRNA of SIK3
- CTL cytotoxic T-lymphocyte
- the (components of) cell-mediated immune response is a pro-inflammatory cytokine, such as TNF.
- the contacting step of such embodiment comprises bringing into contact a first cell and the candidate compound and a pro-inflammatory cytokine, wherein the first cell expresses SIK3 (eg, a protein or mRNA of SIK3).
- the pro-inflammatory cytokine is TNF (such as rHuTNF), optionally brought into contact with the first cell at a concentration of between about 0.01 ng/mL and about 1000 ng/mL.
- TNF such as rHuTNF
- the TNF may be brought into contact with the first cell at a concentration of about 0.05, 0.1, 0.5, 1.0, 5.0, 10, 50, 100, or 500 ng/mL, in particular between about 5 and 50 ng/mL or 50 and 200 ng/mL TNF.
- the first cell is preferably a cell involved with a proliferative disorder (such as a tumour), eg a cell derived from a tumour.
- a proliferative disorder such as a tumour
- the tumour or cell thereof may be one or, or derived from, one of the tumours described elsewhere herein.
- the first cell expresses a mutant form of a SIK, such as a mutant form of SIK3, and/or a mutant form of SIK2 and/or a mutant form of SIK1.
- a mutant form of a SIK such as a mutant form of SIK3, and/or a mutant form of SIK2 and/or a mutant form of SIK1.
- the knock-in SIK mutants as described by Darling et al 2016 may be expressed by the first cell.
- the first cell expresses a shRNA, or comprises a siRNA, that inhibit the expression or activity of a SIK (such as SIK3, SIK2 and/or SIK1). Examples of such shRNA or siRNA sequences are described elsewhere herein.
- Use of recombinant or modified first cells can aid the characterisation of the candidate compound; in particular as to its specificity (or selectivity) towards SIK3 compare to SIK2 and/or SIK1.
- the candidate compound used in the screening methods may be one selected from a polypeptide, peptide, glycoprotein, a peptidomimetic, an antibody or antibody-like molecule (such as an intra-body); a nucleic acid such as a DNA or RNA, for example an antisense DNA or RNA, a ribozyme, an RNA or DNA aptamer, siRNA, shRNA and the like, including variants or derivatives thereof such as a peptide nucleic acid (PNA); a genetic construct for targeted gene editing, such as a CRISPR/Cas9 construct and/or guide RNA/DNA (gRNA/gDNA) and/or tracrRNA; a carbohydrate such as a polysaccharide or oligosaccharide and the like, including variants or derivatives thereof; a lipid such as a fatty acid and the like, including variants or derivatives thereof; or a small organic molecules including but not limited to small molecule ligands, or small cell-per
- the candidate compound is a small molecule, such as one described elsewhere herein.
- the candidate compound is a SIK3 inhibitor, such as one described elsewhere herein.
- the candidate compound inhibits SIK3 preferentially to inhibiting SIK2 and/or SIK1, in particular the candidate compound inhibits SIK3 in the first cell, for example preferentially to inhibiting SIK2 (and/or SIK3) in the second cell.
- Such SIK3 inhibiting candidate compounds may have been identified (or characterised) as a SIK3 inhibitor (such as a SIK3-specific inhibitor, eg a SIK3 selective inhibitor) prior to it being included in a screening method of the invention.
- a candidate compound may, as a prior step, be subjected to a SIK3 (and/or SIK2 or SIK1) biochemical assay - such as those provided by Promega, ProQuinase or ThermoFisher - to identify or characterise that the candidate compound is a SIK3 inhibitor (such as a SIK3-specific inhibitor, eg a SIK3 selective inhibitor).
- Item 1 A method for the treatment of a proliferative disorder in a subject by inhibiting SIK3, the method comprising administering a SIK3 inhibitor to the subject
- Item 2 A method for the treatment of a proliferative disorder in a subject by sensitising cells involved with the proliferative disorder to a cell-mediated immune response, the method comprising administering a SIK3 inhibitor to the subject.
- Item 3 A method for the treatment of a proliferative disorder in a subject, by inhibiting SIK3 and sensitising cells involved with the proliferative disorder to a cell-mediated immune response, the method comprising administering a SIK3 inhibitor to the subject.
- Item 4. The method of any one of items 1 to 3, wherein the proliferative disorder is a tumour, in particular a solid tumour.
- Item 5 The method of item 2 or 3, wherein the cell-mediated immune response is mediated by a pro-inflammatory cytokine-secreting cell, in particular a lymphocyte, and preferably a cytotoxic T lymphocyte (CTL).
- a pro-inflammatory cytokine-secreting cell in particular a lymphocyte, and preferably a cytotoxic T lymphocyte (CTL).
- CTL cytotoxic T lymphocyte
- Item 6 The method of any one of items 2, 3 and 5, wherein the cell-mediated immune response induces killing of cells involved with the proliferative disorder.
- Item 7 The method of any one of items 2, 3, 5 and 6, wherein the cell-mediated immune response involves at least one immune cell effector molecule, in particular one secretable or secreted by an immune cell.
- Item 8 The method of item 7, wherein the effector molecule is a pro-inflammatory cytokine, in particular tumour necrosis factor (TNF).
- Item 9 The method of any one of items 1 to 8, wherein the SIK3 inhibitor is administered to the subject to sensitise cells involved with the proliferative disorder to killing induced by TNF.
- Item 10 The method of any one of items 1 to 9, wherein the SIK3 inhibitor is administered to the subject to sensitise cells involved with the proliferative disorder to apoptosis mediated by tumour necrosis factor receptor 1 (TNFR1)- sig nailing.
- Item 11 The method of any one of items 1 to 10, wherein the SIK3 inhibitor is administered to the subject to induce a reduced amount of cytotoxicity to cells involved with the proliferative disorder in the absence of the cell-mediated immune response.
- TNFR1 tumour necrosis factor receptor 1
- Item 12 The method of any one of items 1 to 11, wherein the administration of the SIK3 inhibitor is associated with impairment of NF-kappaB activity in cells involved with the proliferative disorder, in particular by an enhancement or increase in translocation of NF-kappaB out of the nucleus of the cells involved with the proliferative disorder.
- Item 13 A method for the sensitisation of cells involved with a proliferative disorder to a cell-mediated immune response, the method comprising exposing the cells involved with the proliferative disorder to a SIK3 inhibitor.
- Item 14 A method for the killing of cells involved with a proliferative disorder, the method comprising exposing the cells involved with the proliferative disorder to: (i) TNF, a TNF variant and/or an agonist of TNFRl-signalling; and (ii) a SIK3 inhibitor.
- Item 15 The method of item 1 or 14, wherein the effect is mediated by inhibiting SIK3.
- Item 16 The method of any one of items 1 to 15, wherein SIK3 in the cells involved with the proliferative disorder is inhibited.
- Item 17 The method of any one of items 1 to 16, wherein SIK2 in immune cells is inhibited to a lesser extent than SIK3.
- Item 18 The method of any one of items 1 to 17, wherein SIKlin immune cells is inhibited to a lesser extent than SIK3.
- Item 19 The method of any one of itemsl to 18, wherein the effect is not associated with an increase in the production of one or more anti-inflammatory cytokines and/or is not associated with a decrease in the production of one or more pro-inflammatory cytokines.
- Item 20 The method of any one of items 1 to 19, wherein cells involved with the proliferative disorder are subject to activated TNFR2-signalling.
- Item 21 The method of any one of items 1 to 20, wherein cells involved with the proliferative disorder are exposed to TNF, a TNF variant and/or an agonist of TNFR2 -signalling.
- Item 22 The method of any one of items 1 to 21, wherein the subject has a plasma concentration of TNF greater than about 2 pg/mL.
- Item 23 The method of any one of items 1 to 22, wherein the proliferative disorder is a solid tumour that, in the subject, has an intratumoural concentration of TNF greater than 0.5 pg/mL.
- Item 24 A method for the treatment of a proliferative disorder in a subject, the method comprising exposing cells involved with the proliferative disorder in the subject to: (i) TNF, a TNF variant and/or an agonist of TNFRl- signalling; and (ii) a SIK3 inhibitor.
- Item 25 The method of item 24, wherein the effect is mediated by inhibiting SIK3, and/or by sensitising the cells involved with the proliferative disorder to the cytotoxic effects of TNFR1- or TNFR2 -signalling.
- Item 26 The method of item 24 or 25, wherein the SIK3 inhibitor is administered to the subject.
- Item 27 The method of any one of items 24 to 26, wherein the TNF, TNF variant or the agonist of TNFRl-signalling is administered to the subject.
- Item 28 The method of any one of items 24 to 27, wherein TNF is administered in the subject at a dose of between about 5 and 500 ug/m2/day, in particular between about 20 and 200 ug/m2/day.
- Item 29 The method of any one of items 24 to 27, wherein the TNF variant is a variant form of TNF having higher cytotoxic activity and lower systemic toxicity.
- Item 30 The method of any one of items 24 to 26, wherein an agent that is capable of inducing or induces the exposure of the cells involved with the proliferative disorder to the TNF, TNF variant or the agonist of TNFR1- signalling, is administered to the subject.
- Item 31 The method of item 30, wherein the agent is a virus that is capable of inducing or induces the exposure of the cells involved with the proliferative disorder to the TNF, TNF variant or the agonists of TNFR1- signalling Item 32.
- the agent is an immune cell, in particular wherein the immune cell is administered as part of adoptive cell transfer.
- Item 33 The method of any one of items 24 to 26, wherein the exposure of the cells involved with the proliferative disorder to TNF is induced by a pharmaceutical, therapeutic or other procedure that increases the amount of TNF in the plasma of the subject and/or in the environment of such cells.
- Item 34 The method of item 33, wherein the pharmaceutical, therapeutic or other procedure comprises cancer immunotherapy and/or radiotherapy.
- Item 35 A method for the increase of the therapeutic index of treatment with TNF in a subject being treated therewith for a proliferative disorder, the method comprising administering an inhibitor of SIK3 to the subject.
- Item 36 A method for the sensitisation of a subject suffering from a proliferative disorder to a therapy involving the administration of TNF to the subject, the method comprising administering an inhibitor of SIK3 to the subject.
- Item 37 A method for the reduction in risk of a haematological proliferative disorder in a subject being treated with an anti-TNF agent, the method comprising administering an inhibitor of SIK3 to the subject.
- Item 38 The method of any one of items 1 to 37, wherein the SIK3 inhibitor is a SIK3-specific inhibitor.
- Item 39 The method of any one of items 1 to 38, wherein the SIK3 inhibitor inhibits SIK3 more potently than it inhibits SIK2.
- Item 40 The method of any one of items 1 to 39, wherein the SIK3 inhibitor is selected from a polypeptide, peptide, glycoprotein, a peptidomimetic, an antibody or antibody-like molecule (such as an intra-body); a nucleic acid such as a DNA or RNA, for example an antisense DNA or RNA, a ribozyme, an RNA or DNA aptamer, siRNA, shRNA and the like, including variants or derivatives thereof such as a peptide nucleic acid (PNA); a genetic construct for targeted gene editing, such as a CRISPR/Cas9 construct and/or guide RNA/DNA (gRNA/gDNA) and/or tracrRNA; a hetero-bi- functional compound (such as a PROTAC or a HyT molecule); a carbohydrate such as a polysaccharide or oligosaccharide and the like, including variants or derivatives thereof; a lipid such as a fatty acid and the
- Item 42 The method of any one of items 1 to 40, wherein the SIK3 inhibitor is a small molecule, in particular, a small molecule ligand or a small cell-permeable molecule.
- Item 43 The method of any one of items 1 to 40, wherein the SIK3 inhibitor is dasatinib or a variant thereof.
- Item 44 The method of any one of items 1 to 40, wherein the SIK3 inhibitor is a cyclic compound of the following formula I and salts thereof
- R 6 is alkyl, alkenyl, alkynyl, cycloalkyi, cycloalkylalkyi, cycloalkenyl, cycloalkenylalkyi, aryl, aralkyl, heterocyclo, or heterocycloalkyl, each of which is unsubstituted or substituted with Z l7 Z 2 and one or more (preferably, one or two) groups Z 3 ;
- R 2 and R 3 are each independently:
- (3) -Z 13 -NR 7 R 8 ; (1) are each independently hydrogen or R 6 ;
- (1) are each independently hydrogen or R 6 ;
- R 7 , and Rs may together be alkylene, alkenylene or heteroalkyl, completing a 3- to 8-membered saturated or unsaturated ring with the nitrogen atom to which they are attached, which ring is unsubstituted or substituted with Z l7 Z 2 and Z 3 ; or
- any two of R 9 , Rio and Rn may together be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with Z l7 Z 2 and Z 3 ;
- Rn is:
- Z 6 is (i) alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, alkylaryl, cycloalkylaryl, heterocyclo, or heterocycloalkyl; (ii) a group (i) which is itself substituted by one or more of the same or different groups (i); or (iii) a group (i) or (ii) which is substituted by one or more of the following groups (2) to (16) of the definition of Z l7 Z 2 and Z 3 ;
- any two of Z l7 Z 2 , and Z 3 may together be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached; or
- any two of Z l7 Z 2 , and Z 3 may together be -(CH 2 ) r -0- ,where r is 1 to 5, completing a 4- to 8- membered saturated or unsaturated ring together with the atoms to which they are attached;
- Z 4 and Z 5 are each independently:
- (1) are each independently hydrogen or Z 6 ;
- Z 7 and Z 8 , or Z 6 and Z 10 may together be alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached, which ring is unsubstituted or substituted with Z l7 Z 2 and Z 3 ; or
- Z 7 or Z 8 together with Z 9 , may be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with Z l7 Z 2 and Z 3 ;
- Z n and Z 12 are each independently:
- Item 45 The method of item 44, wherein such SIK3 inhibitor is a variant of dasatinib.
- Item 46 The method of any one of items 1 to 40, wherein the SIK3 inhibitor is selected from the group consisting of:
- Item 47 The method of any one of items 1 to 46, wherein cells involved in the proliferative disorder are resistant against a cell-mediated immune response.
- Item 48 The method of any one of items 1 to 47, wherein cells involved with the proliferative disorder have been subjected to prior immunotherapy, in particular the subject has had prior immunotherapy by administration with an immune checkpoint molecule.
- Item 49 The method of any one of items 1 to 48, wherein cells involved in the proliferative disorder are characterised by expression and/or activity of SIK3, in particular such cells express mRNA and/or protein of SIK3, and/or are positive for such SIK3 expression and/or activity.
- Item 50 The method of any one of items 1 to 49, wherein the proliferative disorder is a tumour selected from the group consisting of: pancreatic cancer, breast cancer, melanoma, ovarian cancer, oesophageal cancer, sarcomoa and colorectal cancer; or cells involved with the proliferative disorder are those of or derived from one of such tumours.
- the proliferative disorder is a tumour selected from the group consisting of: pancreatic cancer, breast cancer, melanoma, ovarian cancer, oesophageal cancer, sarcomoa and colorectal cancer; or cells involved with the proliferative disorder are those of or derived from one of such tumours.
- Item 51 A method for determining whether a subject has, or is at risk of, developing a phenotype that is associated with cellular resistance against a cell-mediated immune response and/or that is associated with expression or activity of SIK3, the method comprising the step of:
- the detection of the applicable biomarker in the sample indicates a phenotype or a risk of developing a phenotype that is associated with cellular resistance against the cell-mediated immune response, and/or that is associated with expression or activity of SIK3, in the subject;
- the applicable biomarker is one selected from the group consisting of:
- SIK3 in particular the presence (or an amount) of or expression and/or activity of SIK3, preferably of phosphorylated SIK3;
- TNFR1 in particular the presence (or an amount) of or expression and/or activity of TNFR1;
- LKB1 in particular the presence (or an amount) of or expression and/or activity of LKB1, preferably of phosphorylated LKB1.
- the detection of the applicable biomarker comprises determining the presence or an amount of SIK3, or activity thereof, in the sample, in particular of phosphorylated SIK3.
- Item 53 The method according to items 51 or 52, further comprising a step of determining the presence or amount of TNF in the sample, wherein the presence of or an amount of TNF in the sample indicates a phenotype or a risk of developing a phenotype that is associated with cellular resistance against the cell-mediated immune response, and/or associated with expression or activity of SIK3, in the subject.
- Item 54 A method for determining whether a subject has, or has a risk of developing, a disease, disorder or condition that is associated with cellular resistance against a cell-mediated immune response and/or that is associated with expression or activity of SIK3, the method comprising the steps of:
- a cell-mediated immune response being (i) immune cells selected from the group consisting of: lymphocytes, T-cells, CTLs and TILs, or (ii) a pro-inflammatory cytokine in particular TNF; and
- an enhancement of the cell-mediated immune response against such cells of the subject indicates that the subject has or has a risk of developing such disease, disorder or condition.
- Item 55 A use of an antigen binding protein (ABP) capable of binding specifically to SIK3 in the in-vitro diagnosis of a disease, disorder or condition in a mammalian subject, in particular of a disease, disorder or condition that is associated with cellular resistance against a cell-mediated immune response, and/or that is associated with expression or activity of SIK3.
- ABSP antigen binding protein
- Item 56 The use according to item 55, wherein the ABP is capable of binding specifically to phosphorylated SIK3.
- a kit comprising: (a) an ABP or a nucleic acid capable of binding specifically to SIK3; and (b) optionally (i) instructions describing how to use the ABP or a nucleic acid or kit for detecting SIK3 in the sample; and/or (ii) one or more other item, component, reagent or other means useful for the use of the kit or the detection of SIK3 in the sample.
- Item 58 The kit according to item 57 comprising an ABP capable of binding specifically to phosphorylated SIK3.
- Item 59 A method for identifying and/or characterising a compound suitable for the treatment of a disease, disorder or condition that is characterised by cellular resistance against a cell-mediated immune response and/or one that is characterised by expression or activity of SIK3, the method comprising the steps of:
- the method according to item 59 wherein the reduction of expression, activity function and/or stability or SIK3 and/or the enhancement in cytotoxicity is identified by reference to a control method selected from a method practiced in the absence of any candidate compound, or a method practised with a compound having a known effect on such expression, function, activity and/or stability, in particular a positive or negative control, and/or a method practiced in the absence of a cell-mediated immune response.
- Item 61 The method according to item 59 or 60, wherein the cell-mediated immune response is a pro-inflammatory cytokine, in particular TNF.
- Item 62 The method according to any one of items 59 to 61, wherein the first cell is a cell involved with a proliferative disorder, in particular a tumour.
- SIK3 inhibitor for use in the treatment of a proliferative disorder in a subject, by inhibiting SIK3 and sensitising cells involved with the proliferative disorder to a cell-mediated immune response, the treatment comprising administering the SIK3 inhibitor to the subject.
- the cell-mediated immune response is mediated by a pro- inflammatory cytokine-secreting cell, in particular a lymphocyte, and preferably a cytotoxic T lymphocyte (CTL) and/or (ii) wherein the cell-mediated immune response involves at least one immune cell effector molecule that is a pro-inflammatory cytokine, in particular tumour necrosis factor (TNF).
- a pro-inflammatory cytokine-secreting cell in particular a lymphocyte, and preferably a cytotoxic T lymphocyte (CTL) and/or
- CTL cytotoxic T lymphocyte
- TNF tumour necrosis factor
- Item A3 The SIK3 inhibitor for use of item Al or A2, wherein: (i) the subject has a plasma concentration of TNF greater than about 2 pg/mL; and/or (ii) the proliferative disorder is a solid tumour that, in the subject, has an intratumoural concentration of TNF greater than 0.5 pg/mL.
- SIK3 inhibitor for use in the treatment of a proliferative disorder in a subject, the treatment comprising exposing cells involved with the proliferative disorder in the subject to: (i) TNF, a TNF variant and/or an agonist of TNFRl-signalling; and (ii) a SIK3 inhibitor, wherein the SIK3 inhibitor is administered to the subject.
- Item A5. The SIK3 inhibitor for use of item A4, wherein: (i) the TNF, TNF variant or the agonist of TNFRl-signalling is administered to the subject; (ii) an agent that is capable of inducing or induces the exposure of the cells involved with the proliferative disorder to the TNF, TNF variant or the agonist of TNFRl-signalling, is administered to the subject; or (iii) the exposure of the cells involved with the proliferative disorder to TNF is induced by a pharmaceutical, therapeutic or other procedure that increases the amount of TNF in the plasma of the subject and/or in the environment of such cells.
- SIK3 inhibitor for use of any one of items Al to A6, wherein the SIK3 inhibitor inhibits SIK3 more potently than it inhibits SIK2.
- SIK3 inhibitor for use of any one of items Al to A7, wherein the SIK3 inhibitor is: (i) an inhibitory nucleic acid; or (ii) a small molecule, in particular, a small molecule ligand or a small cell-permeable molecule.
- SIK3 inhibitor for use of any one of items Al to A8, wherein the SIK3 inhibitor is a cyclic compound of the following formula I and salts thereof
- R 6 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, heterocyclo, or heterocycloalkyl, each of which is unsubstituted or substituted with Z l7 Z 2 and one or more (preferably, one or two) groups Z 3 ;
- R 2 and R 3 are each independently:
- (1) are each independently hydrogen or R 6 ;
- (1) are each independently hydrogen or R 6 ;
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Priority Applications (13)
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CA3097212A CA3097212A1 (en) | 2017-04-20 | 2018-04-20 | Intracellular kinase associated with resistance against anti-tumour immune responses, and uses thereof |
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CN201880041301.5A CN111182924A (en) | 2017-04-20 | 2018-04-20 | Intracellular kinases associated with resistance to anti-tumor immune responses and uses thereof |
US16/316,298 US20210040486A1 (en) | 2017-04-20 | 2018-04-20 | Intracellular kinase associated with resistance against anti-tumour immune responses, and uses thereof |
AU2018253937A AU2018253937A1 (en) | 2017-04-20 | 2018-04-20 | Intracellular kinase associated with resistance against anti-tumour immune responses, and uses thereof |
EP18717947.8A EP3612224A1 (en) | 2017-04-20 | 2018-04-20 | Intracellular kinase associated with resistance against anti-tumour immune responses, and uses thereof |
EP19718396.5A EP3781206A2 (en) | 2018-04-20 | 2019-04-23 | A 5-thiazolecarboxamide kinase inhibitor and uses thereof |
PCT/EP2019/060303 WO2019202160A2 (en) | 2018-04-20 | 2019-04-23 | A 5-thiazolecarboxamide kinase inhibitor and uses thereof |
US17/048,772 US20210179602A1 (en) | 2018-04-20 | 2019-04-23 | A 5-thiazolecarboxamide kinase inhibitor and uses thereof |
JP2023079268A JP2023108628A (en) | 2017-04-20 | 2023-05-12 | Intracellular kinase associated with resistance to anti-tumor immune responses and uses thereof |
AU2024203451A AU2024203451A1 (en) | 2017-04-20 | 2024-05-23 | Intracellular kinase associated with resistance against anti-tumour immune responses, and uses thereof |
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Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2019202160A3 (en) * | 2018-04-20 | 2019-11-28 | Iomx Therapeutics Ag | A 5-thiazolecarboxamide kinase inhibitor and uses thereof |
WO2020083926A1 (en) | 2018-10-23 | 2020-04-30 | Iomx Therapeutics Ag | Heterocyclic kinase inhibitors and uses thereof |
KR20200104083A (en) * | 2019-02-26 | 2020-09-03 | 한국화학연구원 | N-phenyl-2-(pyrimidin-4-ylamino)thiazol-5-carboxamide derivatives, pharmaceutically acceptable salts thereof and a whitening material composition containing the same as an active ingredient |
WO2021032129A1 (en) * | 2019-08-20 | 2021-02-25 | 湖南华纳大药厂股份有限公司 | Kinase inhibitor, preparation therefor, pharmaceutical composition thereof and use thereof |
EP3901151A1 (en) | 2020-04-21 | 2021-10-27 | iOmx Therapeutics AG | Halogenated-heteroaryl and other heterocyclic kinase inhibitors, and uses thereof |
WO2021219731A2 (en) | 2020-04-28 | 2021-11-04 | Iomx Therapeutics Ag | Bicyclic kinase inhibitors and uses thereof |
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WO2023067021A1 (en) | 2021-10-19 | 2023-04-27 | Iomx Therapeutics Ag | A synthesis scheme and procedures for preparing a sik3 inhibitor and intermediates thereof |
CN116813608A (en) * | 2023-06-08 | 2023-09-29 | 英矽智能科技(上海)有限公司 | Thiazole compound and application thereof |
EP4257609A1 (en) | 2022-04-08 | 2023-10-11 | iOmx Therapeutics AG | Combination therapies based on pd-1 inhibitors and sik3 inhibitors |
EP4257132A1 (en) | 2022-04-08 | 2023-10-11 | iOmx Therapeutics AG | Sik3 inhibitors for treating diseases resistant to death receptor signalling |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110396543A (en) * | 2019-04-30 | 2019-11-01 | 广州普世利华科技有限公司 | A kind of tumour associated gene mutation site screening method |
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KR20230084416A (en) * | 2021-12-03 | 2023-06-13 | 연세대학교 산학협력단 | A Composition Immune Checkpoint Inhibition Comprising a WNK3 Inhibitor as an Active Ingredient |
WO2023209634A1 (en) | 2022-04-29 | 2023-11-02 | Rhizen Pharmaceuticals Ag | A dual selective pi3k delta and gamma inhibitors and/or a salt-inducible kinase 3 inhibitor for treating solid tumors |
CN114948860B (en) * | 2022-05-06 | 2023-04-28 | 东南大学 | Supermolecule hydrogel nano material, gel factor, preparation method and application thereof |
Citations (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6002008A (en) | 1997-04-03 | 1999-12-14 | American Cyanamid Company | Substituted 3-cyano quinolines |
WO2000062778A1 (en) | 1999-04-15 | 2000-10-26 | Bristol-Myers Squibb Co. | Cyclic protein tyrosine kinase inhibitors |
US20110318373A1 (en) | 2010-06-25 | 2011-12-29 | Aurigene Discovery Technologies Limited | Immunosuppression modulating compounds |
WO2013136070A1 (en) | 2012-03-13 | 2013-09-19 | University Court Of The University Of Dundee | A sik inhibitor for use in a method of treating an inflammatory and/or immune disorder |
WO2013176915A1 (en) | 2012-05-25 | 2013-11-28 | Roman Galetto | Methods for engineering allogeneic and immunosuppressive resistant t cell for immunotherapy |
WO2014093383A1 (en) | 2012-12-14 | 2014-06-19 | Arrien Pharmaceuticals Llc | Substituted 1h-pyrrolo [2,3-b] pyridine and 1h-pyrazolo [3, 4-b] pyridine derivatives as salt inducible kinase 2 (sik2) inhibitors |
WO2014140313A1 (en) | 2013-03-15 | 2014-09-18 | Oncodesign S.A. | Macrocyclic salt-inducible kinase inhibitors |
WO2014191128A1 (en) | 2013-05-29 | 2014-12-04 | Cellectis | Methods for engineering t cells for immunotherapy by using rna-guided cas nuclease system |
WO2015006492A1 (en) | 2013-07-09 | 2015-01-15 | Dana-Farber Cancer Institute, Inc. | Kinase inhibitors for the treatment of disease |
WO2016014552A2 (en) | 2014-07-21 | 2016-01-28 | The Penn State Research Foundation | Selective automated blossom thinning |
WO2016014551A1 (en) | 2014-07-21 | 2016-01-28 | Dana-Farber Cancer Institute, Inc. | Macrocyclic kinase inhibitors and uses thereof |
WO2016023014A2 (en) | 2014-08-08 | 2016-02-11 | Dana-Farber Cancer Institute, Inc. | Uses of salt-inducible kinase (sik) inhibitors |
WO2016146985A1 (en) | 2015-03-13 | 2016-09-22 | University Of Dundee | Derivatives of 1-[(cyclopentyl or 2-pyrrolidinyl)carbonylaminomethyl]-4-(1,3-thiazol-5-yl) benzene which are useful for the treatment of proliferative, autoimmune or inflammatory diseases |
WO2017043633A1 (en) * | 2015-09-10 | 2017-03-16 | 国立大学法人山梨大学 | Therapeutic agent or treatment method for philadelphia chromosome-positive (ph+) acute lymphocytic leukemia (all) having ikzf1 mutation |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7125875B2 (en) * | 1999-04-15 | 2006-10-24 | Bristol-Myers Squibb Company | Cyclic protein tyrosine kinase inhibitors |
WO2013024144A1 (en) * | 2011-08-16 | 2013-02-21 | Evotec (München) Gmbh | Markers for susceptibility to an inhibitor of an src-family kinase |
-
2017
- 2017-04-20 DK DK17167295.9T patent/DK3391907T3/en active
- 2017-04-20 EP EP17167295.9A patent/EP3391907B8/en active Active
-
2018
- 2018-04-20 SG SG11201909656Y patent/SG11201909656YA/en unknown
- 2018-04-20 JP JP2020508074A patent/JP2020517747A/en active Pending
- 2018-04-20 IL IL270040A patent/IL270040B2/en unknown
- 2018-04-20 WO PCT/EP2018/060172 patent/WO2018193084A1/en unknown
- 2018-04-20 US US16/316,298 patent/US20210040486A1/en active Pending
- 2018-04-20 AU AU2018253937A patent/AU2018253937A1/en not_active Abandoned
- 2018-04-20 EP EP18717947.8A patent/EP3612224A1/en active Pending
- 2018-04-20 CN CN201880041301.5A patent/CN111182924A/en active Pending
- 2018-04-20 CA CA3097212A patent/CA3097212A1/en active Pending
-
2023
- 2023-05-12 JP JP2023079268A patent/JP2023108628A/en active Pending
-
2024
- 2024-05-23 AU AU2024203451A patent/AU2024203451A1/en active Pending
Patent Citations (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6002008A (en) | 1997-04-03 | 1999-12-14 | American Cyanamid Company | Substituted 3-cyano quinolines |
WO2000062778A1 (en) | 1999-04-15 | 2000-10-26 | Bristol-Myers Squibb Co. | Cyclic protein tyrosine kinase inhibitors |
US20110318373A1 (en) | 2010-06-25 | 2011-12-29 | Aurigene Discovery Technologies Limited | Immunosuppression modulating compounds |
WO2013136070A1 (en) | 2012-03-13 | 2013-09-19 | University Court Of The University Of Dundee | A sik inhibitor for use in a method of treating an inflammatory and/or immune disorder |
WO2013176915A1 (en) | 2012-05-25 | 2013-11-28 | Roman Galetto | Methods for engineering allogeneic and immunosuppressive resistant t cell for immunotherapy |
US20160081989A1 (en) * | 2012-12-14 | 2016-03-24 | Arrien Pharmaceuticals Llc | Substituted 1 H-Pyrrolo [2, 3-b] pyridine and 1 H-Pyrazolo [3, 4-b] pyridine Derivatives as Salt Inducible Kinase 2 (SIK2) Inhibitors |
WO2014093383A1 (en) | 2012-12-14 | 2014-06-19 | Arrien Pharmaceuticals Llc | Substituted 1h-pyrrolo [2,3-b] pyridine and 1h-pyrazolo [3, 4-b] pyridine derivatives as salt inducible kinase 2 (sik2) inhibitors |
WO2014140313A1 (en) | 2013-03-15 | 2014-09-18 | Oncodesign S.A. | Macrocyclic salt-inducible kinase inhibitors |
WO2014191128A1 (en) | 2013-05-29 | 2014-12-04 | Cellectis | Methods for engineering t cells for immunotherapy by using rna-guided cas nuclease system |
WO2015006492A1 (en) | 2013-07-09 | 2015-01-15 | Dana-Farber Cancer Institute, Inc. | Kinase inhibitors for the treatment of disease |
WO2016014552A2 (en) | 2014-07-21 | 2016-01-28 | The Penn State Research Foundation | Selective automated blossom thinning |
WO2016014551A1 (en) | 2014-07-21 | 2016-01-28 | Dana-Farber Cancer Institute, Inc. | Macrocyclic kinase inhibitors and uses thereof |
WO2016023014A2 (en) | 2014-08-08 | 2016-02-11 | Dana-Farber Cancer Institute, Inc. | Uses of salt-inducible kinase (sik) inhibitors |
WO2016146985A1 (en) | 2015-03-13 | 2016-09-22 | University Of Dundee | Derivatives of 1-[(cyclopentyl or 2-pyrrolidinyl)carbonylaminomethyl]-4-(1,3-thiazol-5-yl) benzene which are useful for the treatment of proliferative, autoimmune or inflammatory diseases |
WO2017043633A1 (en) * | 2015-09-10 | 2017-03-16 | 国立大学法人山梨大学 | Therapeutic agent or treatment method for philadelphia chromosome-positive (ph+) acute lymphocytic leukemia (all) having ikzf1 mutation |
Non-Patent Citations (102)
Title |
---|
"Remington's Pharmaceutical Sciences", 1980 |
AYDIN ET AL., TURK J MED SCI, vol. 42, 2012, pages 762 |
BALKWILL, NATURE REV CANCER, vol. 9, 2009, pages 361 |
BASS, NATURE, vol. 411, 2001, pages 428 - 429 |
BERNT ET AL., CANCER RES, vol. 65, 2005, pages 4343 |
BERRIEN-ELLIOTT ET AL., CANCER RES, vol. 73, 2013, pages 605 |
BLANK ET AL., CANCER RES, vol. 64, 2004, pages 1140 |
BU ET AL., TRENDS MOL MED, vol. 22, 2016, pages 448 |
CHAMBERS ET AL., ANNU REV IMMUNOL, vol. 19, 2001, pages 565 |
CHANG, ANYEG CHEM INT, vol. 54, 2015, pages 11760 |
CHAREONFUPRASERT ET AL., ONCOGENE, vol. 20, 2011, pages 3570 |
CHEN ET AL., CELL DEATH AND DISEASE, vol. 5, 2014, pages el177 |
CLARK ET AL., PNAS, vol. 109, 2012, pages 16986 |
CYRUS ET AL., CHEM BIO CHEM, vol. 11, 2010, pages 1531 |
DARLING ET AL., BIOCHEM, 2016 |
DE FOUGEROLLES ET AL., CURRENT OPINION IN PHARMACOLOGY, vol. 8, 2008, pages 280 - 285 |
DESMET ET AL., NATURE COMMS, vol. 5, 2014, pages 5237 |
DRAKE ET AL., ADV IMMUNOL, vol. 90, 2006, pages 51 |
DU ET AL., EXP OPIN THERAP TARG, vol. 4, 2015, pages 477 |
DUDLEY ET AL., CLIN CANCER RES, vol. 16, 2010, pages 6122 - 31 |
DUDLEY, CLIN CANCER RES, vol. 16, 2010, pages 6122 - 31 |
EBERSBACH ET AL., J MO BIOL, vol. 372, 2007, pages 172 |
ELBASHIR ET AL., NATURE, vol. 411, 2001, pages 494 - 498 |
ETEMADI ET AL., FEBS J, vol. 280, 2013, pages 5283 |
FERRERO ET AL., AM J PHYSIOL CELL PHYSIOL, vol. 281, 2001, pages 1173 |
FLICK; GIFFORD, J IMMUNOL METHODS, vol. 68, 1984, pages 167 - 75 |
FOGLIETTA ET AL., BONE MARROW TRANSPLANT, vol. 48, 2013, pages 269 |
FRASER ET AL., EXP HEMATOL, vol. 37, 2009, pages 1435 |
FU ET AL., SCI TRANSL MED, vol. 7, no. 283, 2015, pages ra52 |
FUTOSI ET AL., BLOOD, vol. 119, 2012, pages 4981 |
GEBAUER; SKERRA, CURR OPIN CHEM BIOL, vol. 13, 2009, pages 245 |
GRABULOVSKI ET AL., J BIOL CHEM, vol. 282, 2007, pages 3196 |
GUO S; KEMPHUES KJ: "par-1, a gene required for establishing polarity in C. elegans embryos, encodes a putative Ser/Thr kinase that is asymmetrically distributed", CELL, vol. 81, no. 4, 1995, pages 611 - 20, XP002936985, DOI: doi:10.1016/0092-8674(95)90082-9 |
HANAHAN; WEINBERG, CELL, vol. 144, 2011, pages 646 |
HEKIM ET AL., CANCER IMMUNOL, 2017 |
HUANG; DIXIT, CELL RESEARCH, vol. 26, 2016, pages 484 |
HUGO ET AL., CELL, vol. 165, 2016, pages 35 |
JOHNSON ET AL., ANAL CHEM, vol. 84, 2012, pages 6553 |
JORGE E. CORTES ET AL: "Long-term bosutinib for chronic phase chronic myeloid leukemia after failure of imatinib plus dasatinib and/or nilotinib : Third-/fourth-line bosutinib for chronic phase CML", AMERICAN JOURNAL OF HEMATOLOGY, vol. 91, no. 12, 1 December 2016 (2016-12-01), US, pages 1206 - 1214, XP055417212, ISSN: 0361-8609, DOI: 10.1002/ajh.24536 * |
KARABINOS ET AL., PROC. NATL. ACAD. SCI. USA, vol. 98, 2001, pages 7863 - 7868 |
KATOH ET AL., MOL CELL ENDOCRINOL, vol. 217, 2004, pages 109 |
KAUFMAN ET AL., NATURE REV DRUG DISC, vol. 14, 2015, pages 642 |
KHAN FA ET AL.: "CRISPR/Cas9 therapeutics: a cure for cancer and other genetic diseases", ONCOTARGET, 26 May 2016 (2016-05-26) |
KHANDELWAL ET AL., EMBO MOL MED, vol. 7, 2015, pages 450 |
KIM, YG; CHA, J.; CHANDRASEGARAN, S.: "Hybrid restriction enzymes: zinc finger fusions to Fok I cleavage domain", PROC NATL ACAD SCI USA, vol. 93, no. 3, 1996, pages 1156 - 60, XP002116423, DOI: doi:10.1073/pnas.93.3.1156 |
KOIDE; KOIDE, METHODS MOL BIOL, vol. 352, 2007, pages 95 |
KREHENBRINK ET AL., J MOL BIOL, vol. 383, 2008, pages 1058 |
KREUTZMAN ET AL., ONCOIMMUNOLOGY, vol. 3, 2014, pages e28925 |
KRIEGLER ET AL., CELL, vol. 53, 1988, pages 45 - 53 |
LEE ET AL., CHEM BIO CHEM, vol. 8, 2007, pages 2058 |
LEONE ET AL., COMP STRUCT BIOTECH J, vol. 13, 2015, pages 265 |
LIZCANO, J. M. ET AL., EMBO J., vol. 23, 2004, pages 833 - 843 |
LOMBARDI ET AL., J LEUK BIOL, vol. 99, 2016, pages 711 |
LUAN ET AL., CELL METAB, vol. 19, 2014, pages 1058 |
MAUTE ET AL., PNAS, vol. 112, 2015, pages 6506 |
MUSTJOKI ET AL., LEUKEMIA, vol. 23, 2009, pages 1389 |
MUSTJOKI ET AL., LEUKEMIA, vol. 27, 2013, pages 914 |
NIXON ET AL., CURR OPIN DRUG DISCOV DEVEL, vol. 9, pages 261 |
NYGREN, FEBS J, vol. 275, 2008, pages 2668 |
ONCOTARGET, vol. 7, pages 30323 |
OZANNE ET AL., BIOCHEM J, vol. 465, 2015, pages 271 |
PAGE ET AL., ANNU REV MED, vol. 65, 2014, pages 185 |
PENNICA ET AL., NATURE, vol. 312, 1984, pages 724 - 9 |
PLATTEN ET AL., FRONT IMMUN, vol. 5, 2015, pages 673 |
POWDERLY, ANN ONE, vol. 28, no. 5 |
RABINOVICH ET AL., ANNU REV IMMUNOL, vol. 25, 2007, pages 267 |
REDMOND ET AL., CANCER IMMUNOL RES., vol. 2, 2014, pages 142 |
REISSFELDER ET AL., J CLIN INV, vol. 125, 2015, pages 739 |
S CHAROENFUPRASERT ET AL: "Identification of salt-inducible kinase 3 as a novel tumor antigen associated with tumorigenesis of ovarian cancer", ONCOGENE, vol. 30, no. 33, 14 March 2011 (2011-03-14), pages 3570 - 3584, XP055444336, ISSN: 0950-9232, DOI: 10.1038/onc.2011.77 * |
SAKAMOTO ET AL., MOL CELL PROTEOMICS, vol. 2, 2003, pages 1350 |
SAKAMOTO ET AL., PNAS, vol. 98, 2001, pages 8554 |
SANOSAKA ET AL., IMMUNOLOGY, vol. 145, 2015, pages 268 |
SASAGAWA ET AL., DEVELOPMENT, vol. 139, 2012, pages 1153 |
SAVIC N; SCHWANK G, TRANSL RES, vol. 168, 2016, pages 15 |
SCHADE ET AL., IMMUNOBIOLOGY, vol. 111, 2007, pages 1366 |
SEDGER; MCDERMOTT, CYTOKINE & GROWTH FACTOR REVIEWS, vol. 25, 2014, pages 543 |
SELVIK ET AL., PLOS ONE, vol. 9, 2014, pages e112485 |
SILLABER ET AL., BR J HAEMATOL, vol. 144, 2009, pages 195 |
SILVERMAN, NAT BIOTECHNOL, vol. 23, 2005, pages 1556 |
SKALNIAK, ONCOTARGET, vol. 8, 2017, pages 72167 |
SKERRA, FEBS J, vol. 275, 2008, pages 2677 |
SMITH; BAGLIONI, J BIOL CHEM, vol. 262, 1987, pages 6951 - 4 |
SONG ET AL., ONCOTARGET, vol. 6, 2015, pages 21533 |
STRUMPP, DRUG DISCOV TODAY, vol. 13, 2008, pages 695 |
SUNDBERG ET AL., ACS CHEM BIOL, vol. 11, 2016, pages 2105 |
SUNDBERG ET AL., PNAS, vol. 111, 2014, pages 12468 |
T. B. SUNDBERG ET AL: "Small-molecule screening identifies inhibition of salt-inducible kinases as a therapeutic strategy to enhance immunoregulatory functions of dendritic cells", PROCEEDINGS NATIONAL ACADEMY OF SCIENCES PNAS, vol. 111, no. 34, 11 August 2014 (2014-08-11), US, pages 12468 - 12473, XP055444431, ISSN: 0027-8424, DOI: 10.1073/pnas.1412308111 * |
TATUSOVA; MADDEN, FEMS MICROBIOL LETT, vol. 174, 1999, pages 247 - 250 |
TOPALIAN ET AL., NEW ENGL J MED, vol. 366, 2012, pages 2443 |
TRIVEDI ET AL., BIO-PROTOCOL, vol. 6, 2016, pages e1847 |
UEBI ET AL., PLOS ONE, vol. 7, 2012, pages e37803 |
WALKINSHAW ET AL., J BIOL CHEM, vol. 288, 2013, pages 9345 |
WANG; LIN, ACTA PHARMACOL SIN, vol. 28, 2008, pages 1275 |
WEIN ET AL., NATURE COMMUN, vol. 7, 2016, pages 13176 |
WILES MV ET AL., MAMM GENOME, vol. 26, 2015, pages 501 |
WOO ET AL., CANCER RES, vol. 72, 2012, pages 917 |
WU ET AL., LEUKEMIA, vol. 28, 2014, pages 179 |
YAHARA ET AL., NATURE COMMUN, vol. 7, 2016, pages 10959 |
ZAMORE, NAT. STRUCT. BIOL., vol. 8, 2001, pages 746 - 750 |
ZHANG ET AL.: "Cpfl is a single RNA-guided Endonuclease of a Class 2 CRIPR-Cas System", CELL, vol. 163, 2015, pages 759 - 771 |
ZHU ET AL., BIOMED PHARMACOTHER, vol. 63, 2009, pages 509 |
ZITVOGEL ET AL., NAT REV IMMUNOL, vol. 6, 2006, pages 715 |
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