WO2013024282A2 - Composés et leurs utilisations - Google Patents

Composés et leurs utilisations Download PDF

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WO2013024282A2
WO2013024282A2 PCT/GB2012/051978 GB2012051978W WO2013024282A2 WO 2013024282 A2 WO2013024282 A2 WO 2013024282A2 GB 2012051978 W GB2012051978 W GB 2012051978W WO 2013024282 A2 WO2013024282 A2 WO 2013024282A2
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alkyl
optionally substituted
compound
cancer
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WO2013024282A3 (fr
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Gary Newton
Trevor Perrior
Alan Ashworth
Christopher James LORD
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Domainex Limited
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/713—Double-stranded nucleic acids or oligonucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This invention relates to compounds that are inhibitors of one or both of the kinases TBK1 and ⁇ (otherwise referred to as I-kappa-B-kinase-3 (IKK3), or down-regulators of the expression of one or both of TBK1 and ⁇ , and their use in the treatment of cancers that are dependent on the PDkinase-pathway.
  • the invention also relates to methods of diagnosis, methods of determining the susceptibility of a cancer to particular treatments, and methods of determining suitability of particular treatments.
  • the PDkinase signalling pathway is an important cell survival pathway which involves a number of protein kinases, and also lipid kinases of the phosphoinositide 3-kinase (PI3 kinase) family whose primary role is to phosphorylate inositol lipids.
  • PI3 kinase phosphoinositide 3-kinase
  • the phosphorylated inositol lipids subsequently play an important signalling role by membrane recruitment of effectors having phosphoinositide-recognition motifs.
  • PI3 kinases Three different classes of PI3 kinases have been identified. All members of the family share a common function in phosphorylating the 3 ⁇ group of phosphatidylinositols (Ptdlns), however they act preferentially on different Ptdlns substrates.
  • Ptdlns phosphatidylinositols
  • the PI3 kinases that are most commonly implicated in cancer are the class I PI3 kinases (Engleman, 2009).
  • PDkinase signalling by class I PD kinases is driven by the kinase function of the pi 10 catalytic domain which primarily converts PtdIns(4,5)P2 into PtdIns(3,4,5)P 3 .
  • Proteins that contain a pleckstrin homology (PH) domain become associated with the cell membrane by binding to Ptdlns(3, 4,5)P > and when localised here they can become further activated by other proteins.
  • a major pathway for transduction of the downstream signal from PDkinase involves the activation of AKT.
  • AKT becomes associated with the cell membrane via its PH domain, from where it can become activated by phopsphorylation of Threonine 308 and Serine 473 by PDK-1, and the mTOR/Rictor complex (mTorc2), respectively.
  • AKT can then provide a powerful growth/survival signal by phosphorylation of a number of proteins including TSC-2, which indirectly activates the mTOR/Raptor complex (mTorcl), GSK3 and members of the FOXO family of proteins (Engleman, 2009; Stephens et ah, 2005)
  • AKT is the PDkinase pathway downstream effector most widely implicated in cancer
  • AKT independent pathways include the Bruton tyrosine kinase (BTK), the TEC families of non-receptor tyrosine kinases and serum- and glucocorticoid- regulated kinases (SGKs) (Qui et al., Oncogene, 2000, 19, 5651-5661; Vasudevan et al., Cancer Cell, 2009, 16 (1), 21-32).
  • BTK Bruton tyrosine kinase
  • SGKs serum- and glucocorticoid- regulated kinases
  • Receptor tyrosine kinases such as EGFR or Erb-2
  • EGFR or Erb-2 can activate the PI3 kinase pathway by recruiting the regulatory subunit thereby releasing the auto-inhibitory role that this would normally play (Nagata et al., Cancer Cell, 2004, 6(2), 117-27). This mechanism of activation is primarily associated with class IA isoforms (Williams et al., Biochem. Soc. Trans, 2009, 37, 615-626).
  • the pi 10 isoforms can be activated directly by binding to activated Ras proteins. This is the primary mode of activation for pi 10 ⁇ , and may also be required for activation of ⁇ ⁇ (Kang et al, PNAS, 2006, 103 (5) 1289- 1294, Andrews et al, Science Signalling, 2007, 407, cm2, "PDK Class IB Pathway” ).
  • Mutations in the one of the PI3 kinase catalytic subunits can result in constituitive activation of the pathway (Engleman, 2009). Mutations in the regulatory p85 subunit can result in loss of its inhibitory activity and hence constitutive activation of the pathway (Engleman, 2009).
  • PI3 Kinase catalytic subunits may be over-expressed resulting in amplification of signalling through the PI3 kinase pathway (Engleman 2009).
  • Loss or inactivation of key phosphatases such as PTEN which reverse the action of the PI3 kinases by dephophorylating the 3 position of Ptdlns(3, 4,5)P3 can increase flux through the PI3 kinase pathway (Engleman, 2009; Nagata et al , Cancer Cell, 2004, 6(2), 117-27).
  • a downstream kinase such as PDK- 1 or AKT may be over-expressed or possess an activating mutation (Engleman, 2009).
  • Phosphatase and tensin homolog is a key enzyme that inhibits signalling through the PDkinase pathway and it therefore has tumour suppressing effects. Mutation in the PTEN gene (PTEN(-) mutation) inactivates the enzyme and leads to increased flux through the pathway. PTEN is one of the most commonly mutated or lost tumour suppressors in human cancer. PTEN loss has been reported in endometrial cancer (35%) and glioblastoma (54%) as well as in other cancer types such as breast (32%), colo-rectal carcinoma (30%), prostate (27%) and lung cancer (19%) (Frattini et al, Br. J. Cancer, 2007, 97(8), 1139-45; Nagata et al, 2004).
  • Low levels of PTEN are also reported in a number of cancers. This can occur for example as the result of the loss of one functional copy of the PTEN gene, often described as haploinsufficiency. It is believed that low levels of PTEN can contribute significantly to the oncogenic state especially when accompanied by other changes/mutations that are able to further activate the PI3 kinase pathway (Ying et al., Cancer Discovery, 2011, 1 (2), 158-169; Nagata et al., 2004). It has also been shown that receptor tyrosine kinase signalling can deactivate PTEN. It has been shown that part of the mechanism of action of the Erb2 antibody trastuzumab involves inhibition of Src kinase activity.
  • Src kinase is believed to be responsible for deactivating PTEN in breast cancers where Erb2 is over-expressed, by phophorylation of key tyrosine residues on PTEN. Furthermore, loss of PTEN has been shown to be associated with resistance to trastuzumab, and inhibition of PI3 kinase signalling can increase sensitivity to trastuzumab in PTEN deficient cells (Nagata et al., 2004).
  • PBkinases increase flux through the PDkinase pathway, and so PI3 kinase activating mutations are oncogenic, for example mutations classified as PIK3CA (catalytic - alpha polypeptide) leads to enhanced signalling through the pathway.
  • PIK3CA mutation can be found in a range of malignancies such as colon, lung, ovarian, liver, brain, stomach and breast cancers (Samuels et al., Science, 2004, 304(5670), 554; Engleman, 2009). Genetic amplification of PIK3CA is also found in a number of tumour types including head and neck, squamous cell lung carcinoma, cervical, gastric and oesophageal (Engleman, 2009).
  • I-kappa-B-kinase epsilon, ⁇ (also known as ⁇ , I-kappa-B-kinase-3 (IKK3), or inducible I-kappa-B-kinase (IKKi)), and TANK Binding Kinase- 1, TBK1 (also known as T2K or NF-kappa B-activating kinase), are serine-threonine kinases.
  • ⁇ activity has been linked to a number of disease states including cancer and obesity.
  • IKBE gene encoding ⁇
  • ⁇ has also been shown to phosphorylate the estrogen receptor, and its activity has been linked to tamoxifen resistance in breast cancer tumours (Guo et al., The Journal of Biological Chemistry, 2010, 285, 3676-3684).
  • ⁇ is also frequently over-expressed in human ovarian cancer lines and primary tumours.
  • ⁇ over-expression renders cells resistant to cis-platin
  • ⁇ knockdown restores cis-platin sensitivity
  • ⁇ inhibitors may show efficacy in the treatment of certain cancers.
  • TBK1 has been linked to various cancer states although the published literature has not defined its exact role, or the appropriate clinical setting for use of a TBK- 1 inhibitor.
  • the levels of TBK1 mRNA and protein are elevated in certain malignant colon and breast cancer cells.
  • TBK1 is also recruited and activated by the RalB/Sec5 effector complex: in cancer cells, constitutive engagement of this pathway via chronic RalB activation, restricts the initiation of apoptotic programmes.
  • the proto-oncogene KRAS (which encodes the protein K-Ras) is mutated in a wide array of human tumours, most of which are aggressive and respond poorly to standard therapies.
  • the knockdown of TBK1 in a number of K-Ras dependant tumour cell lines has been shown to cause cell death.
  • K- Ras can activate the PI3 kinase pathway it is believed that cell lines which have K-Ras mutations are not necessarily addicted to the PI3 kinase pathway. For example it has been shown in pancreatic ductal adenocarcinoma (PDAC) that low levels of PTEN are also required for activation of the PI3 kinase pathway (Ying et ah, 2011).
  • PDAC pancreatic
  • AKT is a major signalling kinase and is generally considered to be one of the enzymes involved in the PDkinase pathway. Despite this it has been shown that not all tumour cell lines that are dependent on the PDkinase pathway have high levels of activated AKT nor do they all respond to AKT knockdown (Vasudevan et al, 2009). Ou et al.
  • the invention provides a compound that is an inhibitor of one or both of TBKl and ⁇ , or a down-regulator of the expression of one or both of TBKl and ⁇ , for use in a method of treating a cancer that is dependent on the PDkinase pathway. It has surprisingly been found by the current inventors that cancers that are deficient in PTEN activity are sensitive to compounds that are inhibitors of TBKl and ⁇ .
  • cancers which are deficient in PTEN activity are sensitive to down-regulation of the expression of TBKl . From the data obtained by the current inventors, it is anticipated that such cancers are also are sensitive to down-regulation of the expression of ⁇ . It has also been found by the current inventors that cancers with overactive PDkinase signalling are sensitive to TBKl and ⁇ inhibitors. From the data obtained by the current inventors, it is anticipated that cancers with overactive PDkinase signalling are sensitive to down-regulation of the expression of one or both of TBKl and ⁇ .
  • the current inventors found that a human cell line in which both alleles of PTEN had been inactivated was lethally susceptible to siRNA inhibition of TBKl. That result demonstrates that TBKl activity is necessary for the survival of cells that are deficient in PTEN.
  • the inventors also found that TBKl inhibitor compounds were selectively toxic to PTEN (-/-) cell lines over PTEN (+/+) cells lines, showing that TBKl activity is necessary for the survival of cells that are deficient in PTEN, but not for cells that have normally functional PTEN.
  • the inventors have further found that breast tumour cell models that have PTEN and/or PIK3CA defects are more sensitive to TBKl inhibitors than tumour cell models with defects in other genes.
  • a compound that is an inhibitor of one or both of TBKl and ⁇ , or a down-regulator of the expression of one or both of TBKl and ⁇ is effective in the treatment of a cancer that is dependent on the PDkinase pathway.
  • a compound that is an inhibitor of one or both of TBKl and ⁇ , or a down-regulator of the expression of one or both of TBKl and ⁇ is effective in the treatment of a cancer that has a defect in one or both of the PTEN and PIK3CA genes.
  • Figure 1 shows the Normalised Percent Inhibition (NPI) scores following the knockdown of 714 kinase genes with a panel of siRNAs in HCT116 human tumour cells in which both alleles of PTEN had been deactivated (PTEN7-) and HCT116 human tumour cells with wildtype PTEN (PTEN +/+).
  • Figures 2 (a) to (c) show the effects of small molecule dual inhibitors of the kinase domain of TBKl and ⁇ on (PTEN-/-)-HCT116 and (PTEN +/+)-HCT116 human tumour cells, (a) shows the results for DMA-A, (b) shows the results for DMX-B and (c) shows the results for DMX-C.
  • Figure 3 shows the effect on survival fraction for escalating concentrations of the ⁇ / ⁇ inhibitor DMX-C on an ovarian tumour cell line which contains deactivating mutations in the PTEN gene.
  • Figures 3 (b) to (d) show the effects on survival fractions for escalating concentrations of the ⁇ / ⁇ inhibitor DMX-C on breast tumour cell lines which contains deactivating mutations in the PTEN gene.
  • Figure 3 (e) shows the effect on survival fraction for escalating concentrations of the ⁇ / ⁇ ⁇ inhibitor DMX-C on a breast tumour cell lines which contains both deactivating mutations in the PTEN gene and activating mutations in the PIK3CA gene.
  • Figures 4(a) to (c) show the effects on survival fractions for escalating concentrations of the ⁇ / ⁇ ⁇ inhibitor DMX-C on breast tumour cell lines which contains activating mutations in the PIK3CA gene.
  • Figures 5 (a) to (e) show the effects on survival fractions for escalating concentrations of the ⁇ / ⁇ ⁇ inhibitor DMX-C on breast tumour cell lines with wildtype PTEN and PIK3CA genes.
  • Figure 6 shows SF80 (concentration at which 80% of cells survive) and (b) shows SF50 (concentration at which 50% of cells survive) results for DMX-C in cell lines with PTEN and/or PIKCA mutations and those with wild type PTEN and PIKCA.
  • Figure 7 shows the results of a study into TBK1 sensitising to BEZ235 (a dual PDkinase, mTOR inhibitor), the graph shows the survival fraction results for T47D breast tumour cells exposed to various concentrations of BEZ235 in the presence or absence of TBK-1 siRNA , with siRNA targeting PIK3CA used as a positive control.
  • BEZ235 a dual PDkinase, mTOR inhibitor
  • TBK1 and ⁇ have overlapping substrate specificities and it is believed that they have similar binding sites. Accordingly, many compounds that are inhibitors of one of TBK1 and ⁇ ⁇ are also inhibitors of the other. Compounds that are strong inhibitors of both TBK1 and ⁇ are particularly advantageous compounds for use in the current invention.
  • the cancer to be treated may be a cancer that is deficient in PTEN activity.
  • the cancer may have reduced amounts of PTEN, or a level of PTEN function that is lower than PTEN function in normal cells in the individual.
  • Expression levels of PTEN protein can be established by western blotting, or in situ hybridization, using commercially available antibodies to PTEN.
  • the cancer may include at least some cells carrying a loss of function mutation in the PTEN gene. The presence or absence of loss of function mutations may be assessed by determining the presence or absence of one or more mutations or polymorphisms in a nucleic acid sequence encoding at least a portion of the PTEN enzyme.
  • the presence of such mutations can be established by Sanger Sequencing or Next Generation (Massively Parallel or Deep) Sequencing, or the use of mutation- specific PCR assays.
  • the copy number of each gene (and thus loss of heterozygosity in the case of PTEN) can be established by Fluorescent In Situ Hybridisation (FISH).
  • FISH Fluorescent In Situ Hybridisation
  • the cancer may be a cancer that has overactive PBkinase signalling.
  • the level of PBkinase signalling can be assessed by a functional assay known to or readily developed by the person skilled in the art.
  • the cancer may include at least some cells carrying an activating PIK3CA mutation.
  • the presence or absence of an activating PIK3CA mutation may be assessed by determining the presence or absence of one or more mutations or polymorphisms in a nucleic acid sequence encoding at least a portion of the PBkinase pi 10 catalytic subunit.
  • Overactive PB kinase signalling may be detected by an increase in phosphorylation of one or more of the downstream proteins, for example PDK-1 or mTOR. This can be measured in standard assay formats such as the use of a western blot, ELISA or in situ hybridization techniques, which all use commercially available phospho-protein specific antibodies.
  • Cancers with overactive PBkinase signalling include endometrial cancer, glioblastoma, colorectal carcinoma, myeloma and leukemia, and cancers of the breast, prostate, lung (including non small cell lung cancer (NSCLC)), ovary, liver, brain and stomach; in particular, endometrial cancer, glioblastoma, breast cancer, including tamoxifen resistant breast cancer, ovarian cancer, including cis-platin resistant ovarian cancer.
  • NSCLC non small cell lung cancer
  • Compounds of the invention are expected to be particularly useful in the treatment of such cancers.
  • a compound for use in the invention may be a compound that is an inhibitor of one or both of TBK1 and ⁇ .
  • a compound is considered to be an inhibitor of TBK1 if it has an IC 50 for inhibition of TBK-1 of ⁇ 300nM.
  • Preferred compounds have an IC 50 for inhibition of TBK-1 of ⁇ 100nM, particularly ⁇ 50nM, more particularly ⁇ 30nM.
  • the IC 50 for inhibition of TBK-1 can be assessed by assays known to the person skilled in the art, for example a luminescent kinase assay, or a time-resolved fluorescence assay.
  • assays known to the person skilled in the art, for example a luminescent kinase assay, or a time-resolved fluorescence assay.
  • a TBK-1 assay is available from Promega (Promega Corporation, 2800 Woods Hollow Road, Madison, WI53711-5399, USA, or see http://www.promega.com/).
  • An example of an assay is described in the Examples section herein.
  • a compound is considered to be an inhibitor of ⁇ if for inhibition of ⁇ of ⁇ 300nM; Preferred compounds have an IC 50 for inhibition of ⁇ of ⁇ 100nM, particularly ⁇ 50nM, more particularly ⁇ 30nM.
  • the IC 50 for inhibition of ⁇ can be assessed by assays known to the person skilled in the art, for example a luminescent kinase assay, or a time-resolved fluorescence assay.
  • an ⁇ assay is available from Invitrogen (see http://www.invitrogen.com). An example of an assay is described in the Examples section herein.
  • a compound for use in the invention may be selective for TBK1 and/or ⁇ over other kinases, or said compound may also inhibit other kinases. Some compounds have been found to be inhibitors of both TBK1 and ⁇ .
  • Compounds that are inhibitors of one or both of TBK1 and ⁇ include compounds selected from the group consisting of: (a) compounds described in PCT/GB2011/001075 (published as WO2012/010826), that is to say compounds of Formula (I):
  • R 2 represents a phenyl or heteroaryl group which is optionally substituted by one or more substituents independently selected from:
  • R' represents one of the following substituents: OH; N0 2 ; CN; COR c ; O.CO.R c ; C0 2 R b ; NR a .COR c ; NR a C0 2 R b ;
  • R a represents a hydrogen atom or a Ci- 4 alkyl group
  • R b represents a hydrogen atom, a Ci_ 4 alkyl group optionally substituted by a group NR a R a , or a cycloalkyl group in which a C3 ⁇ 4 moiety may be replaced by an oxygen atom or an NR a group
  • R c represents a hydrogen atom, a group -NR a R b , or a Ci_ 4 alkyl group optionally substituted by a group NR a R b ;
  • R and R b together may, when attached to the same nitrogen atom, represent a -(CH 2 )m- group in which a C3 ⁇ 4 moiety may be replaced by an oxygen atom or an -NR a - group;
  • n 4 or 5;
  • n 1 or 2;
  • each of R 3 and R 4 independently represents a hydrogen atom or a Ci- 4 alkyl group; or a salt thereof.
  • Rl , R2, R3, and R5 are independently chosen from the following groups: alkyl, alkylene, alkenyl, alkenylene, alkynyl, carbocycle, cycloalkyl, cycloalkenyl, heterocycle, aryl, heteroaryl, halo, hydro, hydroxyl, alkoxy, alkynyloxy, cycloalkyloxy, heterocycloxy, aryloxy, heteroaryloxy, arylalkoxy, heteroarylalkoxy, mercapto, alkylthio, arylthio, cycloalkylthio, arylalkyl, heteroarylalkyl, heteroarylalkenyl, arylalkynyl, haloalkyl, aldehyde, thiocarbonyl, O-carboxy, C-carboxy, carboxylic acid, ester, C-carboxy salt, carboxyalkyl,
  • R4 is independently chosen from hydro, halo, and an optionally-substituted group chosen from lower alkyl, haloalkyl, alkoxy, arylalkoxy, heteroarylalkoxy, and heterocycloalkoxy;
  • R6 and R7 are independently chosen from hydro, halo, and lower alkyl;
  • preferred compounds of group (b) have an ether group at R5 and are without further substitution at R4, R6 and R7, for example compounds of Formula (Ila):
  • Compound (III) was reported as having activity against both TBK1 and ⁇ .
  • Rl is a 5 or 6 membered cyclic alkyl ring or aromatic cyclic ring, wherein optionally one or more carbons in the ring structure is substituted by an O, N or S;
  • Preferred compounds of group (d) are the compounds:
  • BX-795 has also been reported in, for example, J. Biol. Chem. , 2009, 284(21), 14136-14146.
  • the preferred compounds BX-320 and BX-795 were shown to inhibit TBK1 and ⁇ .
  • R 1 is C 3 _8-cycloalkyl
  • X is O, NR 7 or C 3 _6-heterocycloalkyl
  • R 2 is aryl, heteroaryl, fused or unfused aryl-C 3 _6-heterocycloalkyl or fused or unfused heteroaryI-C 3 _6- heterocycloalkyl, each of which is optionally substituted by one or more substitutents selected from aryl, heteroaryl, Ci_6-alkyl, C 3 _7-cycloalkyl and a group A, wherein said Ci-6-alkyl group is optionally substituted by one or more substituents selected from aryl, heteroaryl, R 10 and a group A, said heteroaryl group is optionally substituted by one or more R ⁇ 10> groups; and wherein said C 3 -6- heterocycloalkyl group optionally contains one or more groups selected from oxygen, sulfur, nitrogen and CO;
  • R 3 is Ci-6-alkyl optionally substituted by one or more substituents selected from aryl, heteroaryl, -NR 4 R 5 , -OR 6 , -NR 7 (CO)R 6 , -NR 7 (CO)NR 4 R 5 , -NR 7 S02R 6 , -NR 7 COOR 7 , - CONR 4 R 5 , C 3 _ 6 -heterocycloalkyl and
  • aryl, heteroaryl and C 3 -6 -heterocycloalkyl groups are each optionally substituted by one or more substituents selected from -Ci_6-alkyl and a group A, wherein said -Ci_6-alkyl group is optionally substituted by one or more substituents selected from aryl, heteroaryl and a group A;
  • A is selected from halogen, hydroxyl, cyano, trifluoromethyl, alkoxy, -N0 2 , -NH 2 , -NR 4 R 5 , -OR 6 , -NR 7 (CO)R 6 , -NR 7 (CO)NR 4 R 5 , -NR 7 COOR 7 , -NR 7 (S0 2 )R 6 , - C0 2 H,
  • each R 4 and R 5 is independently selected from hydrogen, C3_7-cycloalkyl, aryl, heteroaryl, Ci_ 6-alkyl and a C 3 -6-heterocycloalkyl ring optionally further containing one or more groups selected from oxygen, sulfur, nitrogen and CO and optionally substituted by one or more R 10 groups, wherein said Ci_6-alkyl is optionally substituted by one or more substituents selected from halogen, cyano, hydroxyl, aryl, heteroaryl, -NR 8 R 9 , -NR 7 (CO)R 6 , NR 7 COOR 6 , -NR 7 (S0 2 )R 6 , -COOR 6 , -CONR 8 R 9 , OR 10 , -S02R 6 and a C
  • R is Ci-6-alkyl, C3_7-cyloalkyl, C4_7-heteroalkyl, heteroaryl, each of which may be optionally substituted by one of more substituents selected from halogen, R 10 and -NR 8 R 9 ; and R 2 is an aryl or heteroaryl group each of which is optionally substituted by one or more substituents selected from Me, CI, F, CN, NHCOMe, CF 3 , COOH, CONH 2 , OH, NH 2 , NHS0 2 Me, OCF 3 , -NHCOO'Bu, -C0 2 Me, -NMe 2 , 4-methylpiperazin-l-yl, N-morpholinyl, (4-methylpiperazin-l-yl)-CO-, (N-morpholinyl)-CH 2 CH 2 0-, (imidazol-l-yl)-CH 2 - and
  • R 1 is -NR 7 (CO)R u ;
  • R 2 is aryl, heteroaryl, fused aryl-C 3 - 6 -heterocycloalkyl or fused heteroaryl-C 3 -6- heterocycloalkyl, each of which is optionally substituted by one or more substitutents selected from aryl, heteroaryl, Ci_ 6 -alkyl, C 3 _ 6 -heterocycloalkyl and a group A, wherein said Ci-6-alkyl group is in turn optionally substituted by one or more substituents selected from aryl, heteroaryl, C3-6 -heterocycloalkyl and a group A, said heteroaryl group is optionally substituted by one or more R 10 groups; and wherein each C 3 _ 6 -heterocycloalkyl group is optionally substituted by one or more groups selected from Ci_6-alkyl, Ci_6-haloalkyl, and A, and which optionally contains one or
  • A is selected from halogen, hydroxyl, cyano, trifluoromethyl, -NO 2 , -NH 2 , -NR 4 R 5 , -OR 6 , - NR 7 (CO)R 6 , -NR 7 (C0)NR 4 R 5 , -NR 7 COOR 7 , -NR 7 (S0 2 )R 6 , -C0 2 H, -NR 7 (S0 2 )NR 4 R 5 , - COOR 7 , -C0NR 4 R 5 , COR 6 and -S0 2 CH 3 ; each R 4 and R 5 is independently selected from hydrogen, C 3 _7-CycloaIkyI, aryl, heteroaryl, Ci-6-alkyl and a C 3 -6 -heterocycloalkyl ring optionally further containing one or more groups selected from oxygen, sulfur, nitrogen and CO, and optionally substituted by one or more R 1( groups, wherein said Ci- 6 -alkyl is
  • R 4 and R 5 together with the N to which they are attached form a C 3 _6-heterocycloalkyl ring optionally further containing one or more groups selected from oxygen, sulfur, nitrogen and CO, wherein said C 3 _6-heterocycloalkyl ring may be saturated or unsaturated and is optionally substituted with one or more groups selected from NR 8 R 9 and R 10 ; each R 6 is independently selected from Ci_6-alkyl, C 3 _7-cycloalkyl, C 4 _7-heterocycloalkyl, aryl and heteroaryl, each of which may be optionally substituted by one or more substituents selected from halogen, R 10 and -NR 8 R 9 ; each R 7 is selected from hydrogen, Ci_6-alkyl and C 3 _6-cycloalkyl, wherein said Ci_6-alkyl is optionally substituted by one or more halogens; each of R 8 and R 9 is independently selected from hydrogen and Ci-6-alky
  • R 8 and R 9 together with the N to which they are attached form a C 4 -6-heterocycloalkyl ring optionally further containing one or more heteroatoms selected from oxygen and sulfur, wherein said C 4 _6-heterocycloalkyl ring is optionally substituted by one or more R 10 groups; and each R 10 is selected from C 3 -7-cycloalkyl and Ci-6-alkyl optionally substituted by one or more halogens, wherein where R 10 is Ci_6-alkyl and two or more R 10 groups are attached to the same carbon atom, the R 10 groups may be linked to form a spiroalkyl group; and each R 11 is independently selected from Ci-6-alkyl, C 3 _7-cycloalkyl, Ci-6-alkyl-C 3 _7-cycloalkyl, C 4-7 - heterocycloalkyl, aryl and heteroaryl, each of which may be optionally substituted by one or more substituents selected from A.
  • Preferred compounds of Formula (VI) include compounds of Formula (Via):
  • R 2 is selected from aryl or heteroaryl, each of which is optionally substituted by one or more substitutents selected from halo, optionally substituted C 3 _7-heterocycloalkyl, optionally substituted Ci-6-alkyl, heteroaryl, Ci_6-alkyl-C 3 -7 -heterocycloalkyl, CN, NHCO- C 3 -7-heterocycloalkyl, CO-C 3 -7- heterocycloalkyl and NHCO-Ci-6-alkyl, wherein said C 3 -7- heterocycloalkyl is optionally substituted by one or more Ci_6-alkyl or A groups, and said Ci_ 6-alkyl is optionally substituted by one or more halo or NR 4 R 5 groups;
  • R is selected from cyclobutyl, thienyl, cyclopentyl, pyrazinyl, CE -cyclopropyl, sec- butyl, tetrahydrofuranyl, thiazolyl, cyclopropyl, isopropyl, cyclohexyl, CH 2 -cyclopentyl and n-propyl.
  • Compound (VII) was reported as having activity against both TBKl and ⁇ .
  • Compound SUl 1652, of Formula (VIII) disclosed in a poster Wilkinson et ah, "High Throughput Compatible Cellular Assays for Interrogating Toll-Like Receptor Signaling Pathways", Invitrogen, Life Technologies Ltd, 3 Fountain Drive, Inchinnan Business Park Paisley PA4 9RF, UK (www.invitrogen.com).
  • n 0, 1,2, 3, or 4 ;
  • each R 1 which may be the same or different, independently represents H, halogen or a group (X) a (Y) b Z;
  • X represents -O- or -CONH-
  • a is 0 or 1 ;
  • Y represents Ci_ 6 alkylene-
  • b is O or l ;
  • Z represents hydroxy, C 1-6 alkyl, Ci_ 6 haloalkyl, C5-7 heterocyclyl, C 1-6 alkoxyalkyl, C 1-6 haloalkoxyalkyl;
  • R 2 represents a group -(X 1 ) c (Y 1 ) d Z 1 ;
  • X 1 represents -Ci-n alkylene-
  • c is 0 or 1 ;
  • Y represents -0-
  • d is 0 or 1
  • Z 1 represents H, aryl or heteroaryl each of which contains 5-14 ring atoms, Cs_7 heterocyclyl, C5-7 cycloalkyl, C5-7 cycloalkenyl, (each of which aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl may be optionally substituted by one or more substituents independently selected from C 1-6 alkyl, Ci_ 6 haloalkyl, halogen, Ci_6 alkoxy, Ci_6 haloalkoxy, S0 2 R 3 , Ci_ 6 hydroxyalkyl);
  • R 3 represents H or C 1-6 alkyl
  • Preferred compounds have the general of structure (Xa):
  • Z is aryl or heteroaryl each of which is optionally substituted by one of more substituents independently selected from halogen, CF 3 , CH 2 OH, SO 2 CH 3 , CH 3 , OCH 3 .
  • R 6 is Br, CN, CONH 2 or CI
  • R 1 denotes A, -[C(R 3 )( R 4 )] 3 ⁇ 4 Ar, -[C(R 3 )( R 4 )] wheneverHet or --[C(R 3 )( R 4 )] wheneverCyc,
  • R 2 denotes H, A, Hal, CN, -[C(R ) 2 ] sanction-Ar', -[C(R 3 ) 2 ] admir-Het', -[C(R 3 ) 2 ] ceremoni-Cyc, OR 3 or N(R ) 2 ,
  • R 3 denotes H or A
  • R 4 denotes H, A, -[C(R 3 ) 2 ] friendshipOR 3 , -[C(R 3 ) 2 ] sanctionCOOR 3 , -[C(R 3 ) 2 ] sanctionN(R 3 ) 2 or -[C(R 3 ) 2 ] anythingHet,
  • Cyc denotes cycloalkyl having 3, 4, 5, 6 or 7 C atoms
  • Ar denotes phenyl which is unsubstituted or mono-, di- or trisubstituted by Hal, A, -[C(R 3 ) 2 ] legalOR 3 , N(R ) 2 , N0 2 , CN, COOR 3 , CON(R ) 2 , NR 3 COA, NR 3 S0 2 A, COR 3 , S0 2 N(R ) 2 and/or S(0) friendshipA,
  • Ar' denotes phenyl which is unsubstituted or mono-, di- or trisubstituted by Hal, A, OR 3 , N(R ) 2 , SR 3 , N0 2 , CN, COOR 3 , CON(R 3 ) 2 , NR COA, NR S0 2 A, S0 2 N(R ) 2 , S(0) admirA, CO- Het ! , Heti, [C(R 3 ) 2 ] sanctionN(R 3 ) 2 , 0[C(R 3 ) 2 ] socialN(R 3 ) 2 , 0[C(R 3 ) 2 LHet !
  • Het denotes a mono- or bicyclic saturated, unsaturated or aromatic heterocycle having 1 to 4 N, and/or O and/or S atoms which is unsubstituted or mono- or disubstituted by Hal, A, OR 3 , N(R ) 2 , N0 2 , CN, COOR 3 , CON(R ) 2 , NR 3 COA, NR 3 S0 2 A, COR s , S0 2 NR 3 and/or S(0) confrontA, Het' denotes a mono-, bi- or tricyclic saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms which is unsubstituted or may be mono- or disubstituted by Hal, A, OR 3 , N(R 3 ) 2 , SR 3 , N0 2 , CN, COOR 3 , CON(R 3 ) 2 , NR 3 COA, NR 3 S0 2 A, S0 2 N(R
  • Hal denotes F, CI, Br or I
  • N denotes 0, 1 or 2
  • Preferred compounds have the following structures:
  • a compound for use in the invention may be a compound that is a down-regulator of the expression of one or both of TBK1 and ⁇ . Expression of one or both of TBK1 and ⁇ may be down-regulated using anti-sense nucleic acid or RNAi technology, amongst other approaches. The use of these approaches to down-regulate gene expression is now well- established in the art. Anti-sense oligonucleotides may be designed to hybridise to the complementary sequence of nucleic acid, pre-mRNA or mature mRNA, interfering with the production of TBK1 or ⁇ so that its expression is reduced or completely or substantially completely prevented.
  • anti-sense techniques may be used to target control sequences of a gene, e. g. in the 5' flanking sequence, whereby the anti- sense oligonucleotides can interfere with expression control sequences.
  • the construction of anti-sense sequences and their use is described for example in Peyman and Ulman, Chemical Reviews, 1990, 90, 543-584, and Crooke, Ann. Rev. Pharmacol. Toxicol. 1992, 32, 329-376.
  • Oligonucleotides may be generated in vitro or ex vivo for administration or anti-sense RNA may be generated in vivo within cells in which down-regulation is desired.
  • double- stranded DNA may be placed under the control of a promoter in a "reverse orientation" such that transcription of the anti- sense strand of the DNA yields RNA which is complementary to normal mRNA transcribed from the sense strand of the target gene.
  • the complementary anti- sense RNA sequence is thought then to bind with mRNA to form a duplex, inhibiting translation of the endogenous mRNA from the target gene into protein. Whether or not this is the actual mode of action is still uncertain. However, it is established fact that the technique works.
  • the complete sequence corresponding to the coding sequence in reverse orientation need not be used. For example fragments of sufficient length may be used. It is a routine matter for the person skilled in the art to screen fragments of various sizes and from various parts of the coding or flanking sequences of a gene to optimise the level of anti-sense inhibition. It may be advantageous to include the initiating methionine ATG codon, and perhaps one or more nucleotides upstream of the initiating codon. A suitable fragment may have about 14-23 nucleotides, e. g. about 15, 16 or 17.
  • An alternative to anti-sense is to use a copy of all or part of the target gene inserted in sense, that is the same, orientation as the target gene, to achieve reduction in expression of the target gene by co-suppression (see Angell & Baulcombe, The EMBO Journal, 1997, 16(12), 3675- 3684; and Voinnet & Baulcombe, Nature , 1997, 389, 553).
  • RNA interference is a two-step process. First, dsRNA is cleaved within the cell to yield short interfering RNAs (siRNAs) of about 21-23nt length with 5' terminal phosphate and 3' short overhangs (-2nt). The siRNAs target the corresponding mRNA sequence specifically for destruction (Zamore, Nature Structural Biology, 2001, 8, 746-750).
  • RNAi may also be efficiently induced using chemically synthesized siRNA duplexes of the same structure with 3'-overhang ends (Zamore et al., Cell, 2000, 101, 25-33. Synthetic siRNA duplexes have been shown to specifically suppress expression of endogenous and heterologeous genes in a wide range of mammalian cell lines (Elbashir, et al. , Nature, 2001, 411, 494-498). Particular siRNA molecules that find use in the invention include RNAi reagents with the target sequence include:
  • a compound that is an inhibitor of one or both of TBKl and ⁇ , or a down- regulator of the expression of one or both of TBKl and ⁇ may be used as the sole active agent, it is also possible for the compound to be used in combination with one or more further active agents.
  • Such further active agents may be further compounds that are inhibitors of one or both of TBKl and ⁇ , or down-regulators of the expression of one or both of TBKl and ⁇ , or they may be different therapeutic agents, for example agents targeting one of the diseases mentioned above, particularly the same disease as that targeted by the compound of the invention.
  • a further therapeutic agent is selected from the group consisting of inhibitors of mTOR, inhibitors of PDkinase, inhibitors of both mTOR and PDkinase, inhibitors of AKT and inhibitors of PDK1.
  • further therapeutic agents include: UCN01, (NVP)- BAG956, Celecoxib, OSU-03012, BX-795, BX-912, BX-320, AR-12, KP372-1, LY294002, PWT-458, PX-866, CAL-101, XL-147, ZSTK474, GDC-0941, (NVP)-BEZ235, AS-252424, TGX-221, XL-765, wortmannin, PI- 103, Perifosine (KRX-0401), Triciribine (API-2), SR13688, AR-67 (DB-67), AR-42, GSK690693, KP372- 1, A-443654, MK-2206, Rapamycin (Sirolimus
  • Deforolimus (Ridaforolimus, AP-23573), AZD-8055, OSI-027, INK- 128, PP-242. These and further therapeutic agents are described in further detail in Chapell et al, Oncotarget, 2011, 2, 135-164.
  • a compound that is an inhibitor of one or both of TBK1 and IKK8, or a down-regulator of the expression of one or both of TBK1 and ⁇ may be used in combination with an inhibitor of the Ras/Raf/Mek/Erk pathway, in particular in tumours that contain activating mutations in this pathway.
  • Examples of therapeutic agents that inhibit the Ras/Raf/Mek Erk pathway are: Tipifarnib (ZarnestaTM, Rl 15777), Sorafenib (Nexavar®, BAY43-9006), AAL-881, LBT-613, RAF265, XL281, SB-590885, PLX-4720, PLX-4032, L-779,450, GW5074, SB-699393, CI-1040 (PD184352), PD0325901, XL518, Selumtinib (AZD6244, ARRY-142886), RDEA119 (BAY 869766), PD098059, U0126, SL-327. These and further therapeutic agents are described in further detail in Chapell, 2011.
  • the compound of the invention may be co-formulated with the additional agent, or it may be formulated separately and administered consecutively, simultaneously or sequentially with the additional agent.
  • the amount of active ingredient which is required to achieve a therapeutic effect will, of course, vary with the particular compound, the route of administration, the subject under treatment, including the type, species, age, weight, sex, and medical condition of the subject and the renal and hepatic function of the subject, and the particular cancer being treated, as well as its severity.
  • An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.
  • Oral dosages of the present invention when used for the indicated effects, will range between about 0.01 mg per kg of body weight per day (mg/kg/day) to about 100 mg/kg/day, preferably 0.01 mg per kg of body weight per day (mg/kg/day) to 10 mg/kg/day, and most preferably 0.1 to 5.0 mg/kg/day, for adult humans.
  • the compositions are preferably provided in the form of tablets or other forms of presentation provided in discrete units containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • a medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, preferably from about 1 mg to about 100 mg of active ingredient.
  • the most preferred doses will range from about 0.1 to about 10 mg/kg/minute during a constant rate infusion.
  • compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
  • preferred compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • the pharmaceutical formulations according to the invention include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous (bolus or infusion), and intraarticular), inhalation (including fine particle dusts or mists which may be generated by means of various types of metered doses pressurized aerosols), nebulizers or insufflators, rectal, intraperitoneal and topical (including dermal, buccal, sublingual, and intraocular) administration, although the most suitable route may depend upon, for example, the condition and disorder of the recipient.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, pills or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • the present compounds can, for example, be administered in a form suitable for immediate release or extended release. Immediate release or extended release can be achieved by the use of suitable pharmaceutical compositions comprising the present compounds, or, particularly in the case of extended release, by the use of devices such as subcutaneous implants or osmotic pumps.
  • compositions for oral administration include suspensions which can contain, for example, microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavoring agents such as those known in the art; and immediate release tablets which can contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate, calcium sulfate, sorbitol, glucose and/or lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants such as those known in the art.
  • Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
  • Disintegrators include without limitation starch, methylcellulose, agar, bentonite, xanthan gum and the like.
  • the compounds of the invention can also be delivered through the oral cavity by sublingual and/or buccal administration. Molded tablets, compressed tablets or freeze-dried tablets are exemplary forms which may be used.
  • compositions include those formulating the present compound(s) with fast dissolving diluents such as mannitol, lactose, sucrose and/or cyclodextrins. Also included in such formulations may be high molecular weight excipients such as celluloses (avicel) or polyethylene glycols (PEG). Such formulations can also include an excipient to aid mucosal adhesion such as hydroxy propyl cellulose (HPC), hydroxy propyl methyl cellulose (HPMC), sodium carboxy methyl cellulose (SCMC), maleic anhydride copolymer (e.g., Gantrez), and agents to control release such as polyacrylic copolymer (e.g. Carbopol 934).
  • fast dissolving diluents such as mannitol, lactose, sucrose and/or cyclodextrins.
  • high molecular weight excipients such as celluloses (avicel) or polyethylene glycols (P
  • Lubricants, glidants, flavors, coloring agents and stabilizers may also be added for ease of fabrication and use.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • the oral drug components can be combined with any oral, nontoxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
  • Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example saline or water-for-injection, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • compositions for parenteral administration include injectable solutions or suspensions which can contain, for example, suitable non-toxic, parenterally acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid, or
  • compositions for nasal, aerosol or inhalation administration include solutions in saline, which can contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, and/or other solubilizing or dispersing agents such as those known in the art.
  • Formulations for rectal administration may be presented as a suppository with the usual carriers such as cocoa butter, synthetic glyceride esters or polyethylene glycol. Such carriers are typically solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.
  • Formulations for topical administration in the mouth include lozenges comprising the active ingredient in a flavoured basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerine or sucrose and acacia.
  • exemplary compositions for topical administration include a topical carrier such as Plastibase (mineral oil gelled with polyethylene). It should be understood that in addition to the ingredients particularly mentioned above, the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.
  • si ⁇ RNA agents are well known to those skilled in the art, for example as described in Xie et a ⁇ ., Drug Discovery Today, 2006 11 (1-2), 67-73. "Harnessing in vivo siRNA delivery for drug discovery and therapeutic development".
  • the invention provides a compound that is an inhibitor of one or both of TBK1 and ⁇ , or a down-regulator of the expression of one or both of TBK1 and ⁇ , for use in a method of treating a cancer that is dependent on the PDkinase pathway comprising:
  • the cancer may be a cancer as described above.
  • the compound may be a compound as described above.
  • a method of treating cancer in an individual in whom the cancer is dependent on the PDkinase pathway comprising administering to the individual a compound that is an inhibitor of one or both of TBKl and ⁇ , or a down- regulator of the expression of one or both of TBKl and ⁇ .
  • the cancer may be a cancer as described above.
  • the compound may be a compound described above.
  • a method of treating cancer in an individual comprising:
  • the cancer may be a cancer as described above.
  • the compound may be a compound as described above.
  • the invention further provides a method of determining the susceptibility of a cancer in an individual to treatment with a compound that is an inhibitor of one or both of TBKl and ⁇ , or a down-regulator of the expression of one or both of TBKl and ⁇ , comprising determining whether the cancer is dependent on the PDkinase pathway, whereby a dependence on the PDkinase pathway indicates that the cancer in the individual has an increased susceptibility to a compound that is an inhibitor of one or both of TBKl and ⁇ , or a down-regulator of the expression of one or both of TBKl and ⁇ .
  • the cancer may be a cancer as described above.
  • the compound may be a compound as described above.
  • the invention further provides a method of determining a suitable treatment for an individual with a cancer comprising:
  • a suitable treatment whereby a compound that is an inhibitor of one or both of TBKl and ⁇ is suitable in the treatment of an individual with a cancer that is dependent on the PDkinase pathway.
  • the cancer may be a cancer as described above.
  • the compound may be a compound as described above.
  • a method of determining a suitable treatment may including determining that a particular treatment is not suitable in the subject. For example, if a cancer is found not to be dependent on the PDkinase pathway, then an inhibitor of one or both of TBKl and ⁇ might not be suitable in the treatment of the individual.
  • the invention further provides a method of predicting the response of a cancer condition in an individual to a treatment with a compound that is an inhibitor of one or both of TBKl and ⁇ by determining whether the cancer is dependent on the PDkinase pathway.
  • the cancer may be a cancer as described above.
  • the compound may be a compound as described above.
  • a cancer may be identified as dependent on the PDkinase pathway by determining the presence in cancer cells from the individual of one or more variations, for example, polymorphisms or mutations, in a nucleic acid encoding a polypeptide that is a component of the PDkinase pathway.
  • a cancer may be identified as being deficient in PTEN activity by determining the presence in cancer cells from the individual of one or more variations, for example, polymorphisms or mutations, in a nucleic acid encoding a PTEN polypeptide.
  • a cancer may be identified as having overactive PDkinase signalling by determining the presence in cancer cells from the individual of one or more variations, for example, polymorphisms or P1K3CA mutations, in a nucleic acid encoding an overactive PD kinase pi 10 polypeptide.
  • a cancer may be identified as being deficient in PTEN activity by determining the presence in cancer cells from the individual of one or more variations, for example, polymorphisms or mutations, in a nucleic acid encoding a PTEN polypeptide.
  • a cancer may be identified as having overactive PDkinase signalling by determining the presence in cancer cells from the individual of one or more variations, for example, polymorphisms or mutations, in a nucleic acid encoding an PD kinase pi 10 polypeptide, for example PIK3CA, which polymorphisms or mutations cause the PI3 kinase to be overactive, or one or more variations in the nucleic acid controlling expression of a PI3 kinase pi 10 polypeptide, for example PIK3CA, which cause the PI3 kinase to be over-expressed.
  • Sequence variations such as mutations and polymorphisms may include a deletion, insertion or substitution of one or more nucleotides, relative to the wild-type nucleotide sequence.
  • the variation may be a gene amplification.
  • the one or more variations may be in a coding or non-coding region of the nucleic acid sequence and, may reduce or abolish the expression of a negatively regulating pathway component polypeptide, for example PTEN.
  • the variant nucleic acid may encode a variant polypeptide which has reduced or abolished activity or may encode a wild- type polypeptide which has little or no expression within the cell, for example through the altered activity of a regulatory element.
  • a variant nucleic acid may have one, two, three, four or more mutations or polymorphisms relative to the wild-type sequence. Furthermore, a cancer may be determined to be heterozygous or homozygous in mutant forms of one or more components, leading to a dependency on the PDkinase pathway.
  • a particular nucleic acid sequence for example a nucleic acid sequence which has a mutation or polymorphism that reduces or abrogates the expression or activity of a PDkinase pathway component, or that increases the expression or activity of a PDkinase pathway component, as the case may be depending on the role that the component plays in the pathway or its control.
  • sequence information can be retained and subsequently searched without recourse to the original nucleic acid itself.
  • scanning a database of sequence information using sequence analysis software may identify a sequence alteration or mutation.
  • Methods according to some aspects of the present invention may comprise determining the binding of an oligonucleotide probe to nucleic acid obtained from the sample, for example, genomic DNA, RNA or cDNA.
  • the probe may comprise a nucleotide sequence which binds specifically to a nucleic acid sequence which contains one or more mutations or
  • the oligonucleotide probe may comprise a label and binding of the probe may be determined by detecting the presence of the label.
  • a method may include hybridisation of one or more (e. g. two) oligonucleotide probes or primers to target nucleic acid. Where the nucleic acid is double-stranded DNA, hybridisation will generally be preceded by denaturation to produce single- stranded DNA.
  • hybridisation may be as part of a PCR procedure, or as part of a probing procedure not involving PCR.
  • An example procedure would be a combination of PCR and low stringency hybridisation.
  • Binding of a probe to target nucleic acid may be measured using any of a variety of techniques at the disposal of those skilled in the art.
  • probes may be radioactively, fluorescently or enzymatically labelled.
  • Other methods not employing labelling of probe include examination of restriction fragment length polymorphisms, amplification using PCR, RN'ase cleavage and allele specific oligonucleotide probing.
  • Probing may employ the standard Southern blotting technique. For instance, DNA may be extracted from cells and digested with different restriction enzymes. Restriction fragments may then be separated by electrophoresis on an agarose gel, before denaturation and transfer to a nitrocellulose filter. Labelled probe may be hybridised to the DNA fragments on the filter and binding determined.
  • Suitable selective hybridisation conditions for oligonucleotides of 17 to 30 bases include hybridization overnight at 42 °C in 6X SSC and washing in 6X SSC at a series of increasing temperatures from 42 °C to 65 °C.
  • Other suitable conditions and protocols are described in Molecular Cloning: a Laboratory Manual: 3rd edition, Sambrook & Russell (2001) Cold Spring Harbor Laboratory Press NY and Current Protocols in Molecular Biology, Ausubel et al. eds. John Wiley & Sons (1992).
  • Nucleic acid which may be genomic DNA, RNA or cDNA, or an amplified region thereof, may be sequenced to identify or determine the presence of polymorphism or mutation therein.
  • a polymorphism or mutation may be identified by comparing the sequence obtained with the database sequence of the component, as set out above. In particular, the presence of one or more polymorphisms or mutations that cause abrogation or loss of function of the
  • sequence Navigator software may be determined using any one of a range of standard techniques. Sequencing of an amplified product may, for example, involve precipitation with isopropanol, resuspension and sequencing using a TaqFS+ Dye terminator sequencing kit. Extension products may be electrophoresed on an ABI 377 DNA sequencer and data analysed using Sequence Navigator software.
  • a specific amplification reaction such as PCR using one or more pairs of primers may conveniently be employed to amplify the region of interest within the nucleic acid sequence, for example, the portion of the sequence suspected of containing mutations or
  • the amplified nucleic acid may then be sequenced as above, and/or tested in any other way to determine the presence or absence of a mutation or polymorphism which reduces PTEN function, or enhances PDkinase function, or the overall flux through the PDkinase pathway.
  • the polymerase chain reaction has been reviewed, for instance in "PCR protocols; A Guide to Methods and Applications", Eds. Innis et al, 1990, Academic Press, New York, Mullis et al, Cold Spring Harbor Symp; Ehrlich (ed), PCR technology, Stockton Press, NY, 1989; and Ehrlich et al, Science, 1991, 252, 1643-1650.
  • PIK3CA A number of methods have been described for the detection of mutant forms of PIK3CA.
  • the most common activating PIK3CA mutations found in cancer are missense mutations resulting from a single base pair change in either: exon 20, coding the helical domain; or exon 9, coding the kinase domain.
  • Examples of common mutations in exon 20 include the following nucleotide changes (corresponding amino acid changes shown in brackets) A3140G (H1047R), A3150T (H1047L).
  • Examples of common mutation in exon 9 include the following nucleotide changes (corresponding amino acid changes shown in brackets) G1633A (E545K), G1624A (E542K), G1634A (E545G).
  • SSCP single strand conformational polymorphism
  • PIK3CA mutants is the use of allele specific PCR using primers specifically designed against common mutants (H1047L, H1047R, E542K and E545K) using the Amplification Refractory Mutation System (ARMSTM, AstraZeneca) and ScopionsTM (DxS), a fluorescent signalling system that detects PCR products (Board et al., Clinical Chemistry, 2008, 54 (4), 757-760).
  • Amplification Refractory Mutation System AstraZeneca
  • ScopionsTM DxS
  • Colonies which lack a functional ADE2 protein appear red due to the accumulation of the ADE2 substrate (Zhang et al., Oncogene 2000, 19, 4346-4353).
  • Another method for the detection of PTEN deletions involves the use of FISH probes directed at the PTEN-locus on chromosome region 10q23 (Chang et al., Leukemia Research, 2006, 30 262- 265).
  • the presence of one or more variations in a component of the PDkinase pathway may be determined by detecting, in one or more cells of a test sample, the presence of the variant component polypeptide, or the absence or reduced amount of the non-mutated component polypeptide (e.g. detection of the levels of PTEN) which is encoded by the nucleic acid sequence.
  • a method of identifying a cancer cell in a sample from an individual as dependent on the PDkinase pathway may include contacting a sample with a specific binding member directed against a variant (e. g. a mutant) polypeptide component of the pathway, and determining binding of the specific binding member to the sample.
  • Another method of identifying a cancer cell in a sample from an individual as dependent on the PDkinase pathway may include contacting a sample with a specific binding member directed against a phosphorylated polypeptide component of the pathway, and determining binding of the specific binding member to the sample.
  • a preferred phosphorylated polypeptide for this purpose is phospho-PDKl (Vasudevan et ah, 201 1).
  • Binding of the specific binding member to the sample may be indicative of the presence of the variant polypeptide component, or phosphorylated polypeptide component, of the pathway in a cell within the sample.
  • Preferred specific binding molecules for use in aspects of the present invention include antibodies and fragments or derivatives thereof ('antibody molecules').
  • the reactivities of a binding member such as an antibody on normal and test samples may be determined by any appropriate means. Tagging with individual reporter molecules is one possibility.
  • the reporter molecules may directly or indirectly generate detectable, and preferably measurable, signals.
  • the linkage of reporter molecules may be directly or indirectly, covalently, e. g. via a peptide bond or non-covalently. Linkage via a peptide bond may be as a result of recombinant expression of a gene fusion encoding binding molecule (e. g. antibody) and reporter molecule.
  • Antibodies for PTEN are commercially available and can be used to assess the amounts of PTEN using standard techniques such as western blotting.
  • Reverse-phase protein array (RPPA) analysis a high throughput technique that can be used to assess multiple tissue samples, has also been used to assess levels of PTEN protein (Vasudevan et ah, 2011).
  • Antibodies for phophorylated kinases such as phospho-PDK- 1 or phospho-mTOR are readily available from commercial suppliers. Sotiriou et al. have described a signature for PI3 kinase pathway activation in breast cancer samples using microarray analysis, this or similar approaches could also be used for identifying tumours with activation of the PI3 kinase pathway (US2011/0038862).
  • tumours that contain a combination of mutations or transformations to members that can activate the PI3 kinase pathway may also be considered dependant on the PI3 kinase pathway.
  • this could take the form of the combination of a PIK3CA mutation and the loss or low levels of PTEN.
  • it may be the over-expression of a growth factor receptor which can activate the PI3 kinase pathway.
  • a growth factor receptor which can activate the PI3 kinase pathway.
  • ErbB2 in breast cancer in combination with a reduction in the amount of PTEN, or with an activating mutation in PIK3CA.
  • Another example would be in activating mutation in a Ras protein for example K-Ras and a mutation in PIK3CA or a reduction in the amount of PTEN.
  • Compound IC50 values were determined at the apparent Km for ATP (20 ⁇ ) based on a radiometric assay (Invitrogen) using 8 or 10 point curves in duplicate.
  • the final reaction conditions contained 400 nM fluorescein-IkBa substrate (DRHDSGLDSMKDE), 20 ⁇ ATP, 2 nM or 8 nM ⁇ or TBK1 kinase respectively, and 3% DMSO in kinase assay buffer consisting of 50 mM HEPES (pH 7.5), 10 mM MgCl, 1 mM EGTA, 0.01% Brij-35.
  • Compound dilutions were prepared from 10 mM DMSO stocks by dilution into DMSO. Compound dilution series were further diluted in kinase assay buffer to give a 12% DMSO stock, the final concentration in the assay being 3% DMSO.
  • the kinase phosphorylation assay was initiated by the addition of the kinase and the reaction was allowed to proceed for 1 hr or 2.5 hr for ⁇ and TBK-1 kinase respectively. Both conditions were within the linearity of the phosphorylation.
  • the reaction was stopped by the addition of 10 mM EDTA, and phosphorylation was detected after a lhr incubation with 1.5 nM terbium-labelled antibody against phosphorylation at Serine 32 on the IkBa peptide, both in TR-FRET dilution buffer (Invitrogen).
  • the compound DMX-A had an IC 50 for inhibition of ⁇ of ⁇ 30nM; and an IC 50 for inhibition of TBK-1 of ⁇ 30nM.
  • the compounds DMX-A, B and C were tested against a number of enzymes that are generally considered members of the PI3 kinase pathway. DMX-A, B and C showed high levels of selectivity for TBKl and ⁇ over the other enzymes tested: i.e.
  • PDK-1, mTOR, ⁇ , ⁇ , PDKy and AKT-l The assays were performed against ⁇ and TBK-1 as described above.
  • the counterscreening assays were performed using radiolabeled P 33 ATP using the Kinase Hotspot Technology (Reaction Biology Corp). Screening was carried out at the Km for ATP for ⁇ - ⁇ and TBK-1 and at 10 ⁇ ATP for the other enzymes, with the exception of screening of DMX-A against AKT-1 which was screened at ⁇ ATP.
  • PTEN wild type comparator HCT-116 cells Both cell lines were screened with a siRNA library targeting -720 kinases and kinase related genes and the affects of each siRNA on cell viability were assessed.
  • SMARTpool siRNAs were transfected with SMARTpool siRNAs using Dharmafect 3 (DF3- Dharmacon).
  • the siRNA library siARRAY - targeting 714 known and putative human protein kinase genes
  • Each well in this library contained a SMARTpool of four distinct siRNA species targeting different sequences of the target transcript.
  • Each plate was supplemented with siCONTROL (ten wells, Dharmacon (USA)).
  • Cells were transfected with the SMARTpool library, where each well of the 96 well-plate contained a pool of four different siRNAs (a SMARTpool) targeting one gene. After five population doublings, cell viability in each well was estimated by use of a highly sensitive luminescent assay measuring cellular ATP levels (Cell Titre Glo, Promega). To identify loss of viability/failure to proliferate effects in each cell line, luminescence readings from each well were log transformed and then centred by the plate median, to account for plate-to-plate variation common in high- throughput screens. Well position effects were identified and eliminated and the quality of data from each plate estimated by calculating Z' -factors (Zhang et al., J. Biomol.
  • NPI scores normalised percent inhibition
  • PTEN +/+ and PTEN -/- HCT 116 human tumour cell lines wherein a NPI score ⁇ 1 indicates a loss of viability, identified that PTEN null cells were particularly sensitive to the knockdown of TBK-1.
  • the NPI results of this experiment are shown in Figure 1.
  • TBK- 1 siRNAs show a selective lethality towards (PTEN-/-)-HCTl 16 cells.
  • DMX-A and DMX-B were dosed at 24 and 96 hours. After 7 days, cell viability was measured using CellTiter Glo Luminescent Cell Viability Assay (Promega, USA). Surviving fractions were calculated and drug sensitivity curves plotted as previously described (Farmer et ah, Nature, 2005 434 (7035), 917-921).
  • DMX-C cells were dosed every three days after initial plating. After 14 days, cell viability was measured using CellTiter Glo Luminescent Cell Viability Assay (Promega, USA).
  • Figure 2(a) shows the DMX-A results
  • Figure 2(b) shows the DMX-B results
  • Figure 2(c) shows the DMX-C results.
  • a leftward shift for the (PTEN-/-) curve indicates a greater sensitivity of this cell type towards the inhibitors tested.
  • an increased sensitivity of the PTEN null cells to TBK- 1 inhibition is indicated by a leftwards shift of the curve relative to the PTEN +/+ HCT 116 line.
  • Figure 6(a) and (b) show SF80 (concentration at which 80% of cells survive) and SF50 (concentration at which 50% of cells survive) results for cell lines with PTEN and/or PIKCA mutations and those with wild type PTEN and PIKCA.
  • DMX-C shows enhanced sensitivity towards cell lines containing either a PTEN mutation or a PIK3CA mutation compared to cell lines that contain both PTEN and PIK3CA wild-type.
  • STR profiling short tandem repeat profiling was used to verify the origin of the panel of cell lines. 8 STR loci were simultaneously amplified in a multiplex PCR reaction (Promega PowerPlex 1.2 System) and compared with the ATCC database. Where appropriate PTEN gene mutation status was determined by Sanger sequencing and western blot analysis and PIK3CA mutation status defined by Sanger sequencing. All of the cell lines used in the panel were human breast cancer cell lines with the exception of A2780 which is a human ovarian cancer cell line.
  • F- TBKI/IKKE sensitising to BEZ235 T47D cell line was purchased from ATCC (USA) and maintained according to the suppliers instructions. The authenticity of the cell line was verified as described above for panel of tumour cell lines. The sensitivity of this cell line to the PI3 kinase inhibitor BEZ235 was measured in the presence or absence of TBK- 1 siRNA, shown in table 1 below. Cells were reverse transfected with siRNA and after 48 hours exposed to BEZ235. BEZ235 exposure was maintained for 7 days, with BEZ235 being replenished 3 days after the initial dosing.
  • siRNAs Two out of four TBK-1 siRNAs increased sensitivity to BEZ235, in a similar fashion to the positive control siRNA targeting PIK3CA.
  • the siRNAs used were from Dharmacon siGenome® SMARTpool siRNA human protein kinase library. Results of this experiment are shown in Figure 7.
  • Qneg represents the negative control (i.e. no siRNA)
  • PIK3CA represents a positive control targeting PI 3CA
  • TBK_l-4 represents 4 different siRNAs targeting TBKl.

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Abstract

L'invention concerne un composé qui est un inhibiteur d'un ou des deux parmi TBK1 et IKKε, ou un régulateur négatif de l'expression d'un ou des deux parmi TBK1 et IKKε, pour l'utilisation dans une méthode de traitement d'un cancer qui est dépendant de la voie PI3kinase. L'invention concerne en outre une méthode de traitement du cancer chez un individu chez qui le cancer est dépendant de la voie PI3kinase, comprenant l'administration à l'individu d'un composé qui est un inhibiteur d'un ou des deux parmi TBK1 et IKKε, ou un régulateur négatif de l'expression d'un ou des deux parmi TBK1 et IKKε.
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