WO2022171121A1 - 治疗肿瘤的方法和组合 - Google Patents
治疗肿瘤的方法和组合 Download PDFInfo
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- WO2022171121A1 WO2022171121A1 PCT/CN2022/075642 CN2022075642W WO2022171121A1 WO 2022171121 A1 WO2022171121 A1 WO 2022171121A1 CN 2022075642 W CN2022075642 W CN 2022075642W WO 2022171121 A1 WO2022171121 A1 WO 2022171121A1
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- amino
- chromen
- pyrimidin
- pyrazolo
- substituted
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Definitions
- the present application relates to the field of biomedicine, in particular to a method and combination for treating tumors.
- PI3K phosphoinositide 3-kinase signaling pathway
- PI3Ks are members of a unique and conserved family of intracellular lipid kinases that phosphorylate phosphatidylinositol or the 3'-OH group on phosphoinositides.
- the PI3K family includes 15 kinases with distinct substrate specificities, expression patterns, and regulatory patterns.
- Class I PI3Ks (p110 ⁇ , p110 ⁇ , p110 ⁇ , and p110 ⁇ ) are typically activated by tyrosine kinases or G-protein coupled receptors to generate (3,4,5)-phosphatidylinositol triphosphate (PIP3), which engages downstream Effectors, such as those in the AKT/PDK1 pathway, mTOR, Tec family kinases and Rho family GTPases.
- Class II and class III PI3Ks are transported intracellularly by the synthesis of phosphatidylinositol 3-bisphosphate (PI(3)P) and (3,4)-bisphosphate phosphatidylinositol (PI(3,4)P2) play a key role.
- PI3K is a protein kinase that controls cell growth (mTORC1) or monitors genome integrity (ATM, ATR, DNA-PK and hSmg-1).
- PI3K-alpha is the most commonly mutated isoform in cancer and plays a role in insulin signaling and glucose homeostasis (Knight et al Cell (2006) 125(4):733–47; Vanhaesebroeck et al Current Topic Microbiol. Immunol. (2010) 347:1–19).
- PTEN tensin homolog
- PI3K-delta and -gamma are preferentially expressed in leukocytes and are important in leukocyte function. These subtypes also contribute to the development and maintenance of hematological malignancies (Vanhaesebroeck et al Current Topic Microbiol. Immunol. (2010) 347:1–19; Clayton et al J Exp Med. (2002) 196(6):753– 63; Fung-Leung Cell Signal. (2011) 23(4):603-8; Okkenhaug et al. Science (2002) 297(5583):1031-34).
- PI3K-delta is activated by cellular receptors (eg, receptor tyrosine kinases) through interaction with the Sarc homology 2 (SH2) domain of the PI3K regulatory subunit (p85) or through direct interaction with RAS.
- cellular receptors eg, receptor tyrosine kinases
- SH2 Sarc homology 2 domain of the PI3K regulatory subunit
- TGF ⁇ Transforming growth factor beta
- TGF ⁇ is a potent cytokine with significant effects on the immune system.
- the main function of TGF ⁇ in the immune system is to maintain tolerance and initial immune response to foreign pathogens.
- Three isoforms of TGF[beta] have been identified in mammals, namely TGF[beta]1, TGF[beta]2 and TGF[beta]3, of which TGF[beta]1 is the predominant isoform.
- TGF ⁇ is secreted in a latent form, and only a small fraction of the total TGF ⁇ secreted is activated under physiological conditions.
- Most of the biological effects of TGF ⁇ are achieved through the binding of TGF ⁇ to the receptors ALK5 and TGF ⁇ receptor II (TGF ⁇ R2).
- active TGF ⁇ dimers can bind tetrameric ALK5 and TGF ⁇ R2 complexes to initiate signal transduction.
- ALK5 is not required for initial binding of TGF ⁇ , but is required for signal
- PD-1 Programmed death 1
- PD-L1 is a member of the CD28 superfamily. PD-1 is expressed in activated T cells, B cells and myeloid cells, and it has two ligands, programmed death ligand 1 (PD-L1) and PD-L2. PD-L1 interacts with the receptor PD-1 on T cells and plays an important role in the negative regulation of immune responses.
- the expression of PD-L1 protein can be detected in many human tumor tissues.
- the microenvironment of the tumor site can induce the expression of PD-L1 on tumor cells.
- the expressed PD-L1 is beneficial to the occurrence and growth of tumors and induces anti-tumor effects.
- PD-1/PD-L1 pathway inhibitors can block the binding of PD-1 to PD-L1, block negative regulatory signals, and restore the activity of T cells, thereby enhancing the immune response
- TGF- ⁇ Transforming growth factor- ⁇ belongs to the TGF- ⁇ superfamily that regulates cell growth and differentiation.
- TGF-beta signals through a heterotetrameric receptor complex consisting of two type I and two type II transmembrane serine/threonine kinase receptors.
- TGF[beta] can affect many cellular functions, such as cell proliferation, differentiation, cell-cell and cell-matrix adhesion, cell motility, and activation of lymphocytes. (For a review of the role of TGF[beta] in regulating immune responses, see Li et al. (2006) Annu. Rev. Immunol. 24:99-146.) Furthermore, TGF[beta] is believed to induce or mediate the progression of many diseases, such as osteoporosis disease, hypertension, atherosclerosis, cirrhosis, fibrotic diseases of the kidneys, liver, and lungs, and tumor progression.
- diseases such as osteoporosis disease, hypertension, atherosclerosis, cirrhosis, fibrotic diseases of the kidneys, liver, and lungs, and tumor progression.
- TGF ⁇ can enhance chronic inflammation-induced end-organ damage, while TGF ⁇ Antagonists are effective in reducing this damage (Border et al. (1990) Nature 346:371-374; Border et al. (1992) Nature 360:361-364; Isaka et al. (1999) Kidney Int. 55:465-475; Sharma et al. (1996) Diabetes 45: 522; Xin et al (2004) Transplantation 15: 1433; Benigni et al (2003) J. Am. Soc. Nephrol. 14: 1816).
- TGF ⁇ may have a direct inhibitory effect on malignant cells and may increase the production or activity of a range of tumor growth factors and angiogenic factors.
- Tumor immunotherapy mainly uses immunological principles and methods to improve the immunogenicity of tumor cells and the sensitivity to effector cell killing, stimulate and enhance the body's anti-tumor immune response, and use immune cells and effector molecules to infuse the host into the body.
- the immune system kills tumors and inhibits tumor growth. Reducing the toxicity and resistance of tumor drugs and reducing the toxic and side effects are still urgent problems to be solved in tumor therapy.
- a PI3K inhibitor and a second therapeutic agent of choice comprising a PI3K inhibitor and a second therapeutic agent of choice.
- the combination of a PI3K inhibitor and a second therapeutic agent selected from one or more of the following has been found to be synergistic in treating tumors (eg, in reducing cancer cell growth or viability, or both) : Immune checkpoint inhibitor, TGF ⁇ inhibitor, or a combination thereof.
- the combination of a PI3K inhibitor and a second therapeutic agent of choice may allow for lower doses of the PI3K inhibitor, the second therapeutic agent, or both, than the monotherapy doses required to achieve the same therapeutic effect apply.
- the combination may allow the PI3K inhibitor, the second therapeutic agent, or both, to be administered less frequently than when the PI3K inhibitor or the second therapeutic agent is administered as a monotherapy.
- Such combinations may provide beneficial effects, eg, in reducing, preventing, delaying and/or reducing the occurrence of one or more of the following consequences: side effects, toxicity or resistance otherwise associated with administration of higher doses of the agent.
- the application provides a pharmaceutical combination comprising a phosphoinositide 3-kinase (PI3K) inhibitor and a second therapeutic agent, wherein the second therapeutic agent is an immune checkpoint inhibitor, a TGF ⁇ inhibitor, a dual function Immune checkpoint/TGF ⁇ inhibitors or combinations thereof.
- PI3K phosphoinositide 3-kinase
- the inhibitor of the immune checkpoint comprises an agent capable of blocking the interaction of programmed death 1 (PD-1) with programmed death ligand 1 (PD-L1).
- the inhibitor of the immune checkpoint comprises an inhibitor of programmed death ligand 1 (PD-L1) and/or programmed death 1 (PD-1).
- the dual function immune checkpoint/TGF ⁇ inhibitor comprises a dual PD-L1/TGF ⁇ inhibitor, or a dual PD-1/TGF ⁇ inhibitor.
- the pharmaceutical combination comprises:
- the inhibitor of the immune checkpoint comprises nucleic acid (eg, dsRNA, siRNA or shRNA), polypeptide (eg, soluble ligand, antibody or antigen-binding fragment thereof, immunoadhesin, fusion protein) , oligopeptides and other molecules), or compounds.
- nucleic acid eg, dsRNA, siRNA or shRNA
- polypeptide eg, soluble ligand, antibody or antigen-binding fragment thereof, immunoadhesin, fusion protein
- oligopeptides and other molecules oligopeptides and other molecules
- the antibody is selected from the group consisting of: human antibodies, humanized antibodies, chimeric antibodies, multispecific antibodies, monoclonal antibodies, and polyclonal antibodies.
- the antigen-binding fragment is selected from the group consisting of: Fab, Fab', F(ab') 2 , Fv, scFv, diabodies, Fd, dAbs, VHHs, large antibodies and complementarity determining regions (CDRs) Fragment.
- the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising HCDR1, HCDR2 and HCDR3.
- VH heavy chain variable region
- the antibody or antigen-binding fragment thereof further comprises or does not comprise a CH1 domain.
- the antibody or antigen-binding fragment thereof further comprises or does not comprise CH2 and CH3 domains.
- the antibody or antigen-binding fragment thereof further comprises an antibody heavy chain constant region.
- the antibody heavy chain constant region is a human antibody heavy chain constant region.
- the human antibody heavy chain constant region is selected from constant regions derived from the group consisting of IgGl, IgG2, IgG3, IgG4, and variants thereof.
- the antibody or antigen-binding fragment thereof further comprises a light chain variable region (VL) comprising LCDR1, LCDR2, LCDR3.
- VL light chain variable region
- the antibody or antigen-binding fragment thereof further comprises a light chain constant region (CL).
- CL light chain constant region
- the inhibitor of the immune checkpoint comprises an anti-PD-L1 antibody or antigen-binding fragment thereof, or an anti-PD-1 antibody or antigen-binding fragment thereof.
- the anti-PD-L1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region of an antibody
- the heavy chain variable region comprises HCDR1, HCDR2, HCDR3, each of which is associated with the following molecules, respectively HCDR1, HCDR2, HCDR3 have at least about 80% (eg, about 85%, 90% or 95%) sequence identity to: Atezolizumab, Avelumab, BMS-936559, MPDL3280A (RG7446) or durvalumab (MEDI4736).
- the heavy chain variable regions have at least about 80% (eg, about 85%, 90% or 95%) sequence identity to the heavy chain variable regions of the following molecules, respectively: Atezolizumab, Avelumab, BMS-936559, MPDL3280A, or durvalumab.
- the anti-PD-L1 antibody or antigen-binding fragment thereof comprises a heavy chain of an antibody, wherein the heavy chain is at least about 80% (e.g., about 85%, e.g., about 85%, respectively,) 90% or 95%) sequence identity: Atezolizumab, Avelumab, BMS-936559, MPDL3280A, or durvalumab.
- the anti-PD-L1 antibody or antigen-binding fragment thereof further comprises a light chain variable region of an antibody, wherein the light chain variable region comprises LCDR1, LCDR2, LCDR3, each of which is associated with the following Molecules LCDR1, LCDR2, LCDR3 have at least about 80% (eg, about 85%, 90% or 95%) sequence identity to: Atezolizumab, Avelumab, BMS-936559, MPDL3280A or durvalumab.
- the anti-PD-L1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region of an antibody, wherein the heavy chain variable region comprises HCDR1, HCDR2, HCDR3, wherein the light chain can
- the variable region comprises LCDR1, LCDR2, LCDR3, each of which has at least about 80% (eg, about 85%, 90% or 95%) sequence identity to HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, LCDR3, respectively, of the following molecules: Atezolizumab, Avelumab, BMS-936559, MPDL3280A (RG7446) or durvalumab (MEDI4736).
- the light chain variable regions have at least about 80% (eg, about 85%, 90% or 95%) sequence identity to the light chain variable regions of atezolizumab, Avelumab, BMS-936559, MPDL3280A, or durvalumab.
- the anti-PD-L1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region of an antibody, each of which has at least about 80% (eg, about 85%, 90% or 95%) sequence identity: Atezolizumab, Avelumab, BMS-936559, MPDL3280A (RG7446) or durvalumab (MEDI4736).
- the anti-PD-L1 antibody or antigen-binding fragment thereof further comprises a light chain of an antibody, wherein the light chain is at least about 80% (eg, about 85%, respectively) the light chain of the following molecule , 90% or 95%) sequence identity: Atezolizumab, Avelumab, BMS-936559, MPDL3280A, or durvalumab.
- the anti-PD-L1 antibody or antigen-binding fragment thereof comprises heavy and light chains of an antibody that are each at least about 80% (eg, about 85%, 90% or 95%) sequence identity to: Atezolizumab, Avelumab, BMS-936559, MPDL3280A (RG7446) or durvalumab (MEDI4736).
- the anti-PD-L1 antibody or antigen-binding fragment thereof comprises: Atezolizumab, Avelumab, BMS-936559, MPDL3280A, or durvalumab, or an antigen-binding fragment thereof, or a variant or biosimilar thereof, or its combination.
- the anti-PD-L1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region of an antibody
- the heavy chain variable region comprises one or more heavy chain selectable from the group consisting of Variable region CDRs (HCDRs): (a) HCDR1 having at least 70% sequence identity to the amino acid sequence set forth in SEQ ID NO: 1; (b) HCDR2 having at least 70% sequence identity to SEQ ID NO: 2; and (c) HCDR3 having at least 70% sequence identity to SEQ ID NO:3.
- HCDRs Variable region CDRs
- the anti-PD-L1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region of an antibody
- the heavy chain variable region comprises one or more HCDRs selected from the group consisting of: ( a) HCDR1 with the amino acid sequence shown in SEQ ID NO: 1 or HCDR1 obtained by amino acid addition, elimination or substitution reaction with no more than 2 amino acid differences from the amino acid sequence shown in SEQ ID NO: 1; (b) HCDR2 having the amino acid sequence shown in SEQ ID NO: 2 or HCDR2 obtained by amino acid addition, elimination or substitution reaction and having no more than 2 amino acid differences with the amino acid sequence shown in SEQ ID NO: 2; and (c) having The HCDR3 of the amino acid sequence shown in SEQ ID NO: 3 or the HCDR3 obtained by amino acid addition, elimination or substitution reaction with the amino acid sequence shown in SEQ ID NO: 3 differs by no more than 2 amino acids.
- the anti-PD-L1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region of an antibody
- the heavy chain variable region comprises HCDR1, HCDR2, HCDR3 comprising the
- the amino acid sequence shown in ID NO: 1 has at least 70% sequence identity
- the HCDR2 comprises an amino acid sequence that is at least 70% identical to the amino acid sequence shown in SEQ ID NO: 2
- the HCDR3 comprises an amino acid sequence with at least 70% sequence identity to the amino acid sequence shown in SEQ ID NO: 2 :
- the anti-PD-L1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region of an antibody
- the heavy chain variable region comprises HCDR1, HCDR2, HCDR3, and the HCDR1 comprises SEQ ID
- the HCDR2 comprises SEQ ID NO: The amino acid sequence shown in: 2 or the amino acid sequence obtained by amino acid addition, elimination or substitution reaction with the amino acid sequence shown in SEQ ID NO: 2 with no more than 2 amino acid differences
- Described HCDR3 comprises SEQ ID NO: The amino acid sequence shown in 3 or the amino acid sequence obtained by amino acid addition, elimination or substitution reaction has no more than 2 amino acid differences with the amino acid sequence shown in SEQ ID NO: 3.
- the anti-PD-L1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region of an antibody
- the heavy chain variable region comprises an amino acid sequence selected from the group consisting of: (a) SEQ The amino acid sequence set forth in ID NO: 4; (b) an amino acid sequence at least 85%, 90%, 95% or 99% identical to the amino acid sequence set forth in SEQ ID NO: 4; and (c) by addition , the amino acid sequence obtained by the elimination or substitution reaction with the amino acid sequence shown in SEQ ID NO: 4 has 1 or more differences.
- TGF ⁇ inhibitor binds TGF ⁇ 1, TGF ⁇ 2, or TGF ⁇ 3.
- TGF[beta] inhibitor binds TGF[beta] or transforming growth factor beta receptor (TGF[beta]R).
- TGF ⁇ inhibitor binds TGF ⁇ type I receptor (TGF ⁇ RI), TGF ⁇ type II receptor (TGF ⁇ RII) or TGF ⁇ type III receptor (TGF ⁇ RIII).
- the TGF ⁇ inhibitor comprises: 1) an anti-TGF ⁇ antibody or antigen-binding fragment thereof; 2) an anti-TGF ⁇ R antibody or antigen-binding fragment thereof; 3) a small molecule TGF ⁇ inhibitor; 4) comprising transforming growth A protein of factor beta receptor II (TGF ⁇ RII) or a functionally active fragment thereof, or a variant or biosimilar thereof, or a combination thereof.
- TGF ⁇ RII transforming growth A protein of factor beta receptor II
- the anti-TGF ⁇ antibody or antigen-binding fragment thereof comprises a heavy chain variable region of an antibody, wherein the heavy chain variable region comprises HCDR1, HCDR2, HCDR3, each of which is associated with HCDR1 of a Fresolimumab molecule, respectively , HCDR2, HCDR3 have at least about 80% sequence identity.
- the heavy chain variable region has at least about 80% sequence identity with the heavy chain variable region of a Fresolimumab molecule.
- the heavy chain has at least about 80% sequence identity with the heavy chain of a Fresolimumab molecule.
- the anti-TGF ⁇ antibody or antigen-binding fragment thereof comprises a light chain variable region of an antibody
- the light chain variable region comprises LCDR1, LCDR2, LCDR3, each of which is associated with LCDR1 of a Fresolimumab molecule, respectively
- LCDR2, LCDR3 have at least about 80% sequence identity.
- the light chain variable region has at least about 80% sequence identity with the light chain variable region of a Fresolimumab molecule.
- the light chain has at least about 80% sequence identity with the light chain of a Fresolimumab molecule.
- the anti-TGF ⁇ antibody or antigen-binding fragment thereof may comprise: Fresolimumab, or an antigen-binding fragment thereof, or a variant or biosimilar thereof.
- the small molecule TGF ⁇ inhibitor comprises the following compounds: SB525334, SD-208, SB431542, LY2109761, LY2157299, GW788388, RepSox, SIS3, LDN-193189, EW-7197, LY364947, or a combination thereof .
- the TGF ⁇ RII has a wild-type human TGF ⁇ receptor type 2 isoform A sequence (eg, the amino acid sequence of NCBI Reference Sequence (Ref Seq) Accession No. NP_001020018), or has a wild-type human A polypeptide of the TGF ⁇ receptor type 2 isoform B sequence (eg, the amino acid sequence of NCBI Ref Seq Accession No. NP_003233), or a polypeptide having a sequence substantially identical to its amino acid sequence.
- a wild-type human TGF ⁇ receptor type 2 isoform A sequence eg, the amino acid sequence of NCBI Reference Sequence (Ref Seq) Accession No. NP_001020018
- a wild-type human A polypeptide of the TGF ⁇ receptor type 2 isoform B sequence eg, the amino acid sequence of NCBI Ref Seq Accession No. NP_003233
- the TGF ⁇ RII or a functionally active fragment thereof comprises: human TGF ⁇ RII extracellular domain (ECD), any portion of NCBI Ref Seq Accession No. NP_001020018 or NCBI Ref Seq Accession No. NP_003233, or substantially identical to its amino acid sequence sequence.
- ECD human TGF ⁇ RII extracellular domain
- TGF ⁇ RII or functionally active fragment thereof comprises:
- (c) has an amino acid sequence with one or more amino acids added, deleted and/or substituted compared to the amino acid sequence shown in SEQ ID NO:6.
- bifunctional immune checkpoint/TGF ⁇ inhibitor is a fusion protein.
- the PD-L1/TGF ⁇ dual inhibitor or PD-1/TGF ⁇ dual inhibitor is a fusion protein.
- the dual PD-L1//TGF ⁇ inhibitor comprises a PD-L1 targeting moiety and a TGF ⁇ receptor domain comprising transforming growth factor beta receptor II (TGF ⁇ RII ) or a functionally active fragment thereof.
- TGF ⁇ RII transforming growth factor beta receptor II
- the dual PD-L1//TGF ⁇ inhibitor comprises a polypeptide
- the polypeptide comprises at least: (i) the heavy chain variable region of an anti-PD-L1 antibody; and (ii) TGF ⁇ RII or its functionally active fragments.
- the anti-PD-L1 antibody heavy chain variable region comprises HCDR1, HCDR2, HCDR3; wherein the HCDR1 comprises at least about 70% sequence identity to the amino acid sequence set forth in SEQ ID NO:1 Amino acid sequence, the HCDR2 comprises an amino acid sequence with at least about 70% sequence identity to the amino acid sequence set forth in SEQ ID NO:2, and the HCDR3 comprises an amino acid sequence with at least about 70% sequence identity to the amino acid sequence set forth in SEQ ID NO:3 amino acid sequence; or
- HCDR1, HCDR2, and HCDR3 have at least about 80%, about 85%, 90%, 95% or 99% sequence identity with HCDR1, HCDR2, and HCDR3 of the following molecules, respectively: Atezolizumab, Avelumab, BMS-936559, MPDL3280A (RG7446) or durvalumab (MEDI-4736).
- the anti-PD-L1 antibody heavy chain variable region comprises HCDR1, HCDR2, HCDR3, and the HCDR1 comprises the amino acid sequence shown in SEQ ID NO: 1 or by amino acid addition, elimination or substitution
- the amino acid sequence obtained by the reaction has no more than 2 amino acid differences with the amino acid sequence shown in SEQ ID NO: 1;
- the HCDR2 comprises the amino acid sequence shown in SEQ ID NO: 2 or through amino acid addition, elimination or substitution reaction
- the obtained amino acid sequence with the amino acid sequence shown in SEQ ID NO: 2 is no more than 2 amino acid differences;
- the HCDR3 comprises the amino acid sequence shown in SEQ ID NO: 3 or is obtained by amino acid addition, elimination or substitution reaction.
- the resulting amino acid sequence has no more than 2 amino acid differences with the amino acid sequence shown in SEQ ID NO: 3.
- the anti-PD-L1 antibody heavy chain variable region comprises an amino acid sequence selected from the group consisting of: (a) the amino acid sequence shown in SEQ ID NO: 4; (b) the same as SEQ ID NO: : the amino acid sequence shown in 4 has at least about 85%, 90%, 95% or 99% sequence identity; (c) obtained by addition, elimination or substitution reaction with the amino acid sequence shown in SEQ ID NO: 4 An amino acid sequence with 1 or more differences in amino acid sequence; and (d) an amino acid sequence with at least about 80% sequence identity to the heavy chain variable region of Atezolizumab, Avelumab, BMS-936559, MPDL3280A, or durvalumab .
- TGF ⁇ RII or functionally active fragment thereof comprises:
- (c) has an amino acid sequence with one or more amino acids added, deleted and/or substituted compared to the amino acid sequence shown in SEQ ID NO:6.
- polypeptide further comprises a linker linking the C-terminus of the heavy chain variable region of the anti-PD-L1 antibody or antigen-binding fragment thereof to the TGF ⁇ RII or its function
- linker linking the C-terminus of the heavy chain variable region of the anti-PD-L1 antibody or antigen-binding fragment thereof to the TGF ⁇ RII or its function
- the N-termini of the active fragments are linked.
- the polypeptide further comprises CH2, CH3 domains, and the polypeptide comprises, from the N-terminus to the C-terminus, the heavy chain variable region (VH), CH2, CH3 domains and TGF ⁇ RII or its functionally active fragment, the C-terminus of the CH3 domain and the N-terminus of the TGF ⁇ RII or its functionally active fragment are connected by a linker.
- VH heavy chain variable region
- CH2, CH3 domains and TGF ⁇ RII or its functionally active fragment the C-terminus of the CH3 domain and the N-terminus of the TGF ⁇ RII or its functionally active fragment are connected by a linker.
- CH2 domains are derived from IgG.
- the CH2, CH3 domains are all derived from IgGl, IgG2, IgG3 or IgG4.
- linker is a peptide linker
- amino acid sequence of the peptide linker is (G 4 S) x , wherein x is any integer from 3-6.
- the peptide linker comprises an amino acid sequence selected from the group consisting of: (a) the amino acid sequence set forth in SEQ ID NO:5; (b) having the amino acid sequence set forth in SEQ ID NO:5 An amino acid sequence having at least about 85%, 90%, 95% or 99% sequence identity; and (c) an amino acid sequence obtained by addition, elimination or substitution with the amino acid sequence shown in SEQ ID NO: 5 having 1 or More differential amino acid sequences.
- polypeptide comprises an amino acid sequence selected from the group consisting of: (a) the amino acid sequence set forth in SEQ ID NO:7; (b) having at least the amino acid sequence set forth in SEQ ID NO:7 An amino acid sequence of about 85%, 90%, 95% or 99% sequence identity; (c) obtained by addition, elimination or substitution reaction with the amino acid sequence shown in SEQ ID NO: 7 has 1 or more Differential amino acid sequences.
- the PD-L1//TGF ⁇ dual inhibitor comprises two of the aforementioned polypeptides.
- the dual PD-L1/TGF ⁇ inhibitor comprises a first polypeptide and a second polypeptide
- the first polypeptide comprises at least: (i) the heavy chain of an anti-PD-L1 antibody and (ii) TGF ⁇ RII or a functionally active fragment thereof
- the second polypeptide comprises at least the light chain variable region of an anti-PD-L1 antibody
- the heavy chain variable region of the first polypeptide and The light chain variable regions of the second polypeptide are capable of specifically binding PD-L1 when combined.
- the first polypeptide further comprises a linker that connects the C-terminus of the heavy chain variable region of the anti-PD-L1 antibody or antigen-binding fragment thereof to the TGF ⁇ RII or the N-terminus of a functionally active fragment thereof.
- the dual PD-L1/TGF ⁇ inhibitor comprises a first polypeptide and a second polypeptide, wherein:
- the first polypeptide sequentially comprises the heavy chain variable region (VH) of the anti-PD-L1 antibody, the CH1 domain, and TGF ⁇ RII or a functionally active fragment thereof from the N-terminus to the C-terminus, and the C-terminus of the CH1 domain is related to the The N-terminus of the TGF ⁇ RII or its functionally active fragment is connected by a linker; and the second polypeptide comprises a light chain variable region (VL) and a light chain constant region (CL) of an anti-PD-L1 antibody from the N-terminus to the C-terminus ).
- the dual PD-L1/TGF ⁇ inhibitor comprises a first polypeptide and a second polypeptide, wherein:
- the first polypeptide comprises the heavy chain variable region (VH), CH1, CH2, CH3 domains and TGF ⁇ RII or functionally active fragments thereof of the anti-PD-L1 antibody in sequence from the N terminus to the C terminus, and the CH3 domain
- the C-terminus is connected with the N-terminus of the TGF ⁇ RII or its functionally active fragment through a linker
- the second polypeptide comprises the light chain variable region (VL), light chain of an anti-PD-L1 antibody from the N-terminus to the C-terminus constant region (CL).
- linker is a peptide linker
- the first polypeptide has at least about 80% sequence identity to a functionally identical polypeptide of M7824 or SHR-1701.
- the second polypeptide has at least about 80% sequence identity to a functionally identical polypeptide of M7824 or SHR-1701.
- the dual PD-L1/TGF ⁇ inhibitor comprises M7824, SHR-1701, or a variant or biosimilar thereof, or a combination thereof.
- the PI3K inhibitor is a dual PI3K delta/gamma inhibitor.
- the PI3K inhibitor comprises a compound of formula (IA-I), (IA-II), (IA-III), or (IA-IV):
- Each occurrence of R is independently selected from hydrogen, halogen, -OR a , CN, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-8 cycloalkyl and substituted or unsubstituted heterocyclic groups;
- Cy 1 is selected from substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted 3- to 15-membered heterocyclic group having at least one heteroatom selected from N, O and S, Substituted or unsubstituted C6-20 aryl and substituted or unsubstituted monocyclic groups of 5- to 14-membered heteroaryl groups having one or more heteroatoms selected from N, O and S;
- Each occurrence of R a may be the same or different and independently selected from hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted C 1-6 alkyl; -NR c R d , where R c , R d independently selected from hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted C1-6 alkyl and C1-6 alkoxy, and -ORc , wherein Rc is substituted or unsubstituted C 1-6 alkyl;
- n is an integer from 1 to 4.
- q 0, 1 or 2;
- Each occurrence of X is independently selected from CR 3 or N;
- R is independently selected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 Alkoxy, substituted or unsubstituted C 2-10 alkenyl, substituted or unsubstituted C 2-12 alkynyl, substituted or unsubstituted C 6-20 aryl, substituted or unsubstituted Substituted C 6-20 aryl C 1-8 alkyl, substituted or unsubstituted C 3-20 cycloalkyl, substituted or unsubstituted C 3-20 cycloalkyl C 1-8 alkane base, substituted or unsubstituted C 3-8 cycloalkenyl C 1-8 alkyl, substituted or unsubstituted C 3-8 cycloalkenyl, substituted or unsubstituted with one or more 5- to 14-membered heteroaryl with
- the PI3K inhibitor comprises a compound of formula (IA-V):
- R is independently selected from hydrogen, halogen, -OR a , CN, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or Unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-8 cycloalkyl and substituted or unsubstituted heterocyclic groups;
- a 3-10 membered ring including carbon atoms bound to R1 and R2, the ring may optionally include one or more heteroatoms that are the same or different and selected from O, NR a and S;
- Each occurrence of X is independently selected from CR 3 or N;
- Each occurrence of R is independently selected from hydrogen, hydroxy, halogen, carboxy, cyano, nitro, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkane oxy, substituted or unsubstituted C 2-10 alkenyl, substituted or unsubstituted C 2-12 alkynyl, substituted or unsubstituted C 6-20 aryl, substituted or unsubstituted Substituted C 6-20 aryl C 1-8 alkyl, substituted or unsubstituted C 3-20 cycloalkyl, substituted or unsubstituted C 3-20 cycloalkyl C 1-8 alkyl , substituted or unsubstituted C 3-8 cycloalkenyl C 1-8 alkyl, substituted or unsubstituted C 3-8 cycloalkenyl, substituted or unsubstituted with one or more options 5- to 14-membered heteroary
- R 5 is hydrogen, C 1-6 alkyl or halogen
- the PI3K inhibitor comprises a compound of formula (IA-VI):
- Each occurrence of R is independently selected from hydrogen, halogen, -OR a , CN, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-8 cycloalkyl and substituted or unsubstituted heterocyclic groups;
- Each occurrence of X is independently selected from CR 3 or N;
- Each occurrence of R is independently selected from hydrogen, hydroxy, halogen, carboxy, cyano, nitro, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkane oxy, substituted or unsubstituted C 2-10 alkenyl, substituted or unsubstituted C 2-12 alkynyl, substituted or unsubstituted C 6-20 aryl, substituted or unsubstituted Substituted C 6-20 aryl C 1-8 alkyl, substituted or unsubstituted C 3-20 cycloalkyl, substituted or unsubstituted C 3-20 cycloalkyl C 1-8 alkyl , substituted or unsubstituted C 3-8 cycloalkenyl C 1-8 alkyl, substituted or unsubstituted C 3-8 cycloalkenyl, substituted or unsubstituted with one or more options 5- to 14-membered heteroary
- R 5 is hydrogen, C 1-6 alkyl or halogen
- n 0, 1, 2, 3, or 4;
- P is 0, 1, 2, 3, 4 or 5.
- R is hydrogen, halogen, substituted or unsubstituted Ci_6 alkyl, or OR a .
- Cy 1 is selected from:
- R 1 and R 2 each independently represent hydrogen or substituted or unsubstituted C 1-6 alkyl.
- R is iodo, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted Substituted or unsubstituted heteroaryl.
- X is CR 3 and each occurrence of R 3 is independently hydrogen, halogen, hydroxy, or NH 2 .
- the PI3K inhibitor comprises:
- the PI3K inhibitor comprises: 2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromene-4 - Ketones, or their enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers, or isotopic variants; or pharmaceutically acceptable salts, solvates thereof , hydrate or prodrug.
- the PI3K inhibitor is (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chrome En-4-one or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.
- the pharmaceutical combination includes a dual PD-L1/TGF ⁇ inhibitor and a PI3K inhibitor.
- the dual PD-L1/TGF ⁇ inhibitor comprises an anti-PD-L1 antibody or an antigen-binding fragment thereof and TGF ⁇ RII or a functionally active fragment thereof.
- the PD-L1/TGF ⁇ dual inhibitor comprises two polypeptides, wherein the polypeptides comprise an amino acid sequence selected from the group consisting of: (a) the amino acid sequence shown in SEQ ID NO:7; (b) an amino acid sequence having at least 85%, 90%, 95% or 99% sequence identity with the amino acid sequence shown in SEQ ID NO: 7; (c) obtained by addition, elimination or substitution reaction with SEQ ID NO: 7
- the amino acid sequence shown in ID NO: 7 has 1 or more different amino acid sequences.
- the PI3K inhibitor is a dual PI3K delta/gamma inhibitor.
- the PI3K inhibitor is (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chrome En-4-one or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.
- the dual PD-L1/TGF ⁇ inhibitor and the PI3K inhibitor are not mixed with each other in the pharmaceutical combination.
- the dual PD-L1/TGF ⁇ inhibitor and the PI3K inhibitor are each independently present in separate containers.
- the pharmaceutical combination may further include a third active substance.
- the third active substance can be selected from vincristine, vinblastine, vindesine, etoposide, docetaxel, paclitaxel, irinotecan, vinorelbine, mitoxantre Any one of quinone, vinflunine, and topotecan or any combination thereof.
- the present application provides a pharmaceutical composition
- a pharmaceutical composition comprising the aforementioned PI3K inhibitor and a second therapeutic agent, and optionally one or more pharmaceutically acceptable carriers or excipients.
- the second therapeutic agent is the aforementioned dual PD-L1/TGF ⁇ inhibitor.
- the PI3K inhibitor is the aforementioned dual PI3K delta/gamma inhibitor.
- the second therapeutic agent and the PI3K inhibitor are present in a single or separate dosage form.
- the present application provides a method for treating and/or preventing tumors, comprising administering to a subject in need thereof: an effective amount of the aforementioned pharmaceutical combination or the aforementioned pharmaceutical composition.
- the method comprises administering to a subject in need thereof: an effective amount of the aforementioned PI3K inhibitor and the aforementioned inhibitor of immune checkpoints. In certain embodiments, the method comprises administering to a subject in need thereof: an effective amount of the aforementioned PI3K inhibitor and the aforementioned TGF ⁇ inhibitor. In certain embodiments, the method comprises administering to a subject in need thereof: an effective amount of the aforementioned PI3K inhibitor, the aforementioned TGF ⁇ inhibitor, and the aforementioned inhibitor of immune checkpoints.
- the method comprises administering to a subject in need thereof: an effective amount of the aforementioned PI3K inhibitor and the aforementioned dual PD-L1/TGF ⁇ inhibitor.
- the PI3K inhibitor is administered concurrently with the dual PD-L1/TGF ⁇ inhibitor.
- the PI3K inhibitor is administered after the dual PD-L1/TGF ⁇ inhibitor.
- the PI3K inhibitor is administered before the dual PD-L1/TGF ⁇ inhibitor.
- it also includes administering to a subject in need thereof an effective amount of the aforementioned small molecule TGF ⁇ inhibitor.
- the tumor includes solid tumors and non-solid tumors.
- the tumor comprises a tumor with abnormal PI3K expression.
- the tumor comprises a tumor with abnormal PD-L1 expression.
- the tumor comprises a tumor with aberrant expression of TGF[beta].
- the tumor comprises a gastrointestinal tumor, melanoma, or lymphoma.
- the tumor is delayed in resistance to the PI3K inhibitor.
- MRD minimal residual disease
- the present application provides the use of the aforementioned pharmaceutical combination or the aforementioned pharmaceutical composition in the preparation of a medicament for treating and/or preventing tumors.
- the use of the aforementioned PI3K inhibitors and the aforementioned inhibitors of immune checkpoints in the preparation of medicaments for treating and/or preventing tumors For example, the use of the aforementioned PI3K inhibitor and the aforementioned TGF ⁇ inhibitor in the preparation of a medicament for treating and/or preventing tumors.
- the present application provides the aforementioned pharmaceutical combination or the aforementioned pharmaceutical composition for treating and/or preventing tumors.
- the present application provides a method of inhibiting tumor growth, the method comprising contacting the tumor with the aforementioned pharmaceutical combination or the aforementioned pharmaceutical composition.
- the contacting is in an in vitro or ex vivo environment.
- the method comprises contacting the tumor with the aforementioned PI3K inhibitor and the aforementioned inhibitor of immune checkpoints. In certain embodiments, the method comprises contacting the tumor with the aforementioned PI3K inhibitor and the aforementioned TGF ⁇ inhibitor. In certain embodiments, the method comprises contacting the tumor with the aforementioned PI3K inhibitor, the aforementioned inhibitor of an immune checkpoint, and the aforementioned TGF ⁇ inhibitor.
- the present application provides a method of inhibiting tumor growth, the method comprising contacting the tumor with the aforementioned PI3K inhibitor and the aforementioned dual PD-L1/TGF ⁇ inhibitor.
- the present application provides a kit comprising: (1) a first container, and the aforementioned PI3K inhibitor located in the first container; (2) a second container, and located in the first container The aforementioned dual PD-L1/TGF ⁇ inhibitor in two containers.
- the present application provides a kit, which may include: (1) a first container, and the aforementioned PI3K inhibitor located in the first container; (2) a second container, and located in the first container The aforementioned inhibitor of immune checkpoint or the aforementioned TGF ⁇ inhibitor in the second container.
- the kit further comprises (3) a third container, and the aforementioned inhibitor of immune checkpoint or the aforementioned TGF ⁇ inhibitor located in the third container, the agent in the third container Different from the medicament in the second container.
- the dosage form of the drug in the kit is an oral dosage form or an injection dosage form.
- the kit also contains instructions.
- Figures 1A-1F show the results of combined administration of CN401 (Tenalisib) (150 mg/kg) and CN202 (WBP1126) (5 mg/kg) in an A20 mouse B-cell lymphoma animal model.
- Figures 2A-2F show the results of combined administration of CN401 (Tenalisib) (150 mg/kg) and CN202 (WBP1126) (15 mg/kg) in an A20 mouse B-cell lymphoma animal model.
- Figures 3A-B show the results of combined administration of CN401 (Tenalisib) (150 mg/kg) and CN202 (WBP1126) (5 mg/kg)/(15 mg/kg) in an A20 mouse B-cell lymphoma animal model.
- Figures 4A-4F show the results of combined administration of CN202 (WBP1126) (5 mg/kg) and CN401 (Tenalisib) (150 mg/kg) in an A20 mouse B-cell lymphoma animal model.
- Figures 5A-5F show the results of combined administration of CN202 (WBP1126) (5 mg/kg) and Alpelisib (50 mg/kg) in an A20 mouse B-cell lymphoma animal model.
- Figures 6A-6F show the results of combined administration of CN401 (Tenalisib) (150 mg/kg) and anti-PD-L1 antibody (Atezolizumab) (5 mg/kg) in an A20 mouse B-cell lymphoma animal model.
- Figures 7A-7B show CN401 (Tenalisib) (150 mg/kg), CN202 (WBP1126) (15 mg/kg) and nab-pac (10 mg/kg) in mouse EMT-60 (mouse breast cancer) cell) tumor growth curve and body weight growth curve.
- Figures 8A-8G show tumor growth curves of mouse EMT-60 (mouse breast cancer cells) in different administration groups.
- PI3K inhibitor or “PI3K inhibitor” generally refers to any inhibitor of PI3K.
- PI3Ks are members of a unique and conserved family of intracellular lipid kinases that phosphorylate phosphatidylinositol or the 3'-OH group on phosphoinositides.
- the PI3K family includes kinases with different substrate specificities, expression patterns, and regulatory patterns (see, eg, Katso et al, 2001, Annu. Rev. Cell Dev. Biol. 17, 615-675; Foster, F.M. et al, 2003, J Cell Sci 116, 3037-3040).
- Class I PI3Ks (eg, p110 ⁇ , p110 ⁇ , p110 ⁇ , and p110 ⁇ are typically activated by tyrosine kinases or G-protein coupled receptors to generate PIP3, which binds downstream mediators such as those in the Akt/PDK1 pathway, mTOR, the Tec family Kinases and Rho family GTPases.
- Class II PI3Ks (eg, PI3K-C2 ⁇ , PI3K-C2 ⁇ , PI3K-C2 ⁇ ) and class III PI3Ks (eg, Vps34) are synthesized in PI(3)P and PI(3,4)P2 in It plays a key role in intracellular trafficking.
- PI3K inhibitors inhibit PI3K-alpha, PI3K-beta, PI3K-gamma, and PI3K-delta isoforms or combinations thereof.
- the PI3K inhibitor can be the dual PI3K delta/gamma inhibitor Tenalisib, 2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromene-4 - Ketones, the structural formula of which is as follows:
- the PI3K inhibitor can be the PI3K inhibitor Alpelisib, (2S)-1-N-[4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl ) pyridin-4-yl]-1,3-thiazol-2-yl]pyrrolidine-1,2-dicarboxamide, its structural formula is as follows:
- a PI3K inhibitor generally refers to a compound that inhibits one or more PI3K isoforms with an IC50 of less than about 1000 nM, less than about 900 nM, less than about 800 nM, less than about 700 nM, less than about 600 nM, less than about 500 nM, Less than about 400 nM, less than about 300 nM, less than about 200 nM, less than about 100 nM, less than about 75 nM, less than about 50 nM, less than about 25 nM, less than about 20 nM, less than about 15 nM, less than about 10 nM, less than about 10 nM, less than about 5 nM, or less than about 1nM.
- alkyl generally refers to a straight or branched chain consisting only of carbon atoms and hydrogen atoms, free of unsaturation, having 1-8 carbon atoms and connected to the remainder of the molecule by a single bond Hydrocarbon radicals such as methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl and 1,1-dimethylethyl (tert-butyl).
- (C 1-6 )alkyl refers to an alkyl group as defined above having up to 6 carbon atoms.
- alkenyl generally refers to a straight or branched aliphatic hydrocarbon group containing a carbon-carbon double bond and possibly having from about 2 to about 10 carbon atoms, such as vinyl, 1-propenyl , 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl and 2-butenyl.
- ( C2-6 )alkenyl refers to an alkenyl group as defined above having up to 6 carbon atoms.
- alkynyl generally refers to a straight or branched chain hydrocarbon group having at least one carbon-carbon triple bond and having 2 to 12 carbon atoms (currently preferred are groups having 2 to 10 carbon atoms). groups), such as ethynyl, propynyl and butynyl.
- groups such as ethynyl, propynyl and butynyl.
- ( C2-6 )alkynyl refers to an alkynyl group as defined above having up to 6 carbon atoms.
- alkoxy generally refers to an alkyl, cycloalkyl, cycloalkylalkyl group attached to the rest of the molecule through an oxygen bond as defined above.
- substituted alkoxy refers to an alkoxy group wherein the alkyl group is substituted (ie, -O-(substituted alkyl)), wherein the term “substituted alkyl” is the same as the term “substituted alkyl” above for " Alkyl” has the same definition.
- alkoxy refers to the group -O-alkyl, including 1-8 carbon atoms in straight chain, branched chain, cyclic configurations, and combinations thereof attached to the parent structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropoxy and cyclohexyloxy.
- cycloalkyl generally refers to non-aromatic mono- or polycyclic ring systems of about 3-12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
- polycyclic cycloalkyl groups include perhydronaphthyl, adamantyl and norbornyl groups, bridged ring groups and spiro groups such as spiro(4,4)nonan-2-yl.
- ( C3-8 )cycloalkyl refers to a cycloalkyl group as defined above having up to 8 carbon atoms.
- cycloalkylalkyl generally refers to a group containing about 3 to 8 carbon atoms directly attached to an alkyl group which in turn results in a stable structure formed from the alkyl group. Ring-containing groups attached to the main structure at any carbon atom, such as cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl.
- cycloalkenyl generally refers to ring-containing groups containing about 3 to 8 carbon atoms with at least one carbon-carbon double bond, such as cyclopropenyl, cyclobutenyl, and cyclopentene base.
- cycloalkenylalkyl refers to a ring-containing group attached directly to an alkyl group, which in turn is attached to the primary structure at any carbon atom from the alkyl group that results in the formation of a stable structure.
- aryl generally refers to aromatic groups having 6-20 carbon atoms, such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, and biphenyl.
- arylalkyl generally refers to an aryl group as defined above attached directly to an alkyl group as defined above, eg -CH2C6H5 and -C2H5C6 H5 .
- heterocycle generally refers to a non-aromatic 3-15 membered ring group consisting of carbon atoms and at least one heteroatom selected from nitrogen, phosphorus, oxygen and sulfur.
- a heterocyclyl group may be a mono-, bi-, tri- or tetracyclic ring system, which may include fused, bridged, or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen, or Sulfur atoms can be optionally oxidized to various oxidation states.
- nitrogen atoms can be optionally quaternized.
- a heterocyclyl group can be attached to the main structure at any heteroatom or carbon atom that results in the formation of a stable structure.
- heterocyclyl generally refers to a heterocyclic-type cyclyl group as defined above. Heterocyclic-type ring groups can be attached to the main structure at any heteroatom or carbon atom that results in the formation of a stable structure.
- heterocyclylalkyl generally refers to a heterocyclic-type ring group as defined above directly bonded to an alkyl group.
- a heterocyclylalkyl group can be attached to the primary structure at a carbon atom in the alkyl group that results in the formation of a stable structure.
- heterocycloalkyl groups include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, Isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidyl, 2-oxopyrrolidinyl, oxazolidine base, piperidinyl, piperazinyl, 4-piperidinyl, pyrrolidinyl, pyrazolidine, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, sulfur morpholinyl, thiamorpholinyl, 1-oxo-
- heteroaryl generally refers to an optionally substituted 5-14 membered aromatic ring having one or more heteroatoms selected from N, O, and S as ring atoms.
- Heteroaryl groups can be mono-, bi- or tricyclic ring systems.
- heterocycle or “heteroaryl” groups include, but are not limited to, oxazolyl, thiazolyl, imidazolyl, pyrrolyl, furyl, pyridyl, pyrimidinyl, pyrazinyl, benzofuranyl , indolyl, benzothiazolyl, benzoxazolyl, carbazolyl, quinolinyl, isoquinolinyl, azetidinyl, acridinyl, benzodioxolyl, benzodi oxanyl, benzofuranyl, carbazolyl, cinnolinyl, dioxolane, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazine base, phthalazinyl, pteridyl, purinyl, quina
- a heteroaryl ring group can be attached to the main structure at any heteroatom or carbon atom that results in the formation of a stable structure.
- substituted heteroaryl also includes ring systems substituted with one or more oxide (-O-) substituents (eg, pyridyl N-oxide).
- heteroarylalkyl generally refers to a heteroaryl ring group as defined above bonded directly to an alkyl group.
- a heteroarylalkyl group can be attached to the primary structure at any carbon atom from the alkyl group that results in the formation of a stable structure.
- ring generally refers to a ring containing 3-10 carbon atoms.
- Immune checkpoints generally refers to a group of molecules on the cell surface of CD4 cells and CD8 T cells. These molecules can effectively act as “brakes” to downregulate or suppress antitumor immune responses.
- Immune checkpoint molecules include but are not limited to programmed cell death 1 (PD-1), programmed cell death ligand 1 (PD-L1), programmed cell death ligand 2 (PD-L2), lymphocyte activation gene- 3 (LAG-3; also known as CD223), Galectin-3, B and T lymphocyte attenuator (BTLA), T-cell membrane protein 3 (TIM3), Galectin-9 (GAL9), B7 -H1, B7-H3, B7-H4, T-cell immunoreceptors with Ig and ITIM domains (TIGIT/Vstm3/WUCAM/VSIG9), V-domain Ig inhibitor of T-cell activation (VISTA), Glucocorticoid-induced tumor necrosis factor receptor-related (GITR) protein,
- PD-1 programme
- inhibitor of an immune checkpoint generally refers to a molecule that inhibits, reduces or interferes with the activity of inhibitory checkpoint molecules.
- inhibitory checkpoint molecules downregulate immune responses (eg, T-cell activation) by delivering negative signals to T cells upon their binding by ligands or counterreceptors.
- the checkpoint inhibitors used with the methods and compositions provided herein can directly inhibit the activity of the inhibitory checkpoint molecule or reduce the expression of the inhibitory checkpoint molecule or interfere with the inhibitory checkpoint molecule and Interaction of binding partners (eg, ligands).
- inhibitors of immune checkpoints include, but are not limited to, proteins, polypeptides, peptides, antisense oligonucleotides, antibodies, antibody fragments, or RNA molecules (eg, targeting the expression of inhibitory checkpoint molecules) inhibitory RNA molecules). Its inhibition can be performed at the DNA, RNA or protein level.
- inhibitory nucleic acids eg, dsRNA, siRNA, or shRNA
- dsRNA dsRNA, siRNA, or shRNA
- the inhibitor of the inhibitory signal is a polypeptide that binds to an immune checkpoint, eg, a soluble ligand (eg, PD-1-Ig), an antibody or antigen-binding fragment thereof; - Antibodies or fragments thereof that bind to L1, PD-L2, CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 and/or TGFR ⁇ or a combination thereof.
- an immune checkpoint eg, a soluble ligand (eg, PD-1-Ig), an antibody or antigen-binding fragment thereof; - Antibodies or fragments thereof that bind to L1, PD-L2, CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 and/or TGFR ⁇ or a combination thereof.
- TGF ⁇ RII or "TGF ⁇ receptor II” generally refers to a protein having a wild-type human TGF ⁇ receptor type 2 isoform A sequence (eg, the amino acid sequence of NCBI Reference Sequence (Ref Seq) Accession No. NP_001020018).
- Polypeptides, or polypeptides having a wild-type human TGF ⁇ receptor type 2 isoform B sequence (such as the amino acid sequence of NCBI Ref Seq Accession No. NP_003233) or a polypeptide having a sequence substantially identical to their amino acid sequence.
- TGF ⁇ RII can retain at least 0.1%, 0.5%, 1%, 5%, 10%, 25%, 35%, 50%, 75%, 90%, 95%, or 99% of the binding activity of the wild-type sequence TGF ⁇ .
- TGF ⁇ RII fragment capable of binding TGF ⁇ generally refers to NCBI Ref Seq Accession No. NP_001020018 or NCBI Ref Seq Accession No. NP_003233 or any portion of substantially identical sequence thereto, the fragment length is at least 20 (eg at least 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 175, or 200) amino acids and retain at least a portion of the TGF ⁇ binding activity of the wild-type receptor or wild-type fragment thereof (e.g., at least 0.1%, 0.5%, 1%, 5%, 10%, 25%, 35%, 50%, 75%, 90%, 95% or 99%). Typically, these fragments are soluble fragments.
- One of the exemplary fragments is the TGF ⁇ RII ectodomain having the sequence of SEQ ID NO:6.
- substantially identical generally means that the polypeptide exhibits at least 50%, preferably 60%, 70%, 75% or 80%, more preferably 85%, 90% or 95%, and most preferably 99% of the reference amino acid sequence % amino acid sequence identity (identity).
- the length of the comparison sequences is generally at least 10 amino acids, preferably at least 15 contiguous amino acids, at least 20, 25, 50, 75, 90, 100, 150, 200, 250, 300 or 350 contiguous amino acids, more preferably, full length amino acid sequence.
- algorithms suitable for determining percent sequence identity and percent sequence similarity may be the BLAST and BLAST 2.0 algorithms, see Altschul et al. (1977) Nucleic Acids Res. 25:3389 and Altschul et al. (1990) J. Mol. Biol. 215, respectively : 403.
- TGF ⁇ inhibitor generally refers to a substance that inhibits the production and signal transduction of TGF ⁇ signaling molecules, and the inhibitor can be a small molecule compound or a macromolecule compound (such as an antibody).
- exemplary small molecule TGF ⁇ inhibitors include SB525334, SD-208, SB431542, LY2109761, LY2157299 (Galunisertib), GW788388, RepSox, SIS3, LDN-193189, EW-7197, and LY364947, among others.
- antibody generally refers to an immunoglobulin reactive against a specified protein or peptide or fragment thereof.
- Antibodies can be antibodies from any class, including but not limited to IgG, IgA, IgM, IgD, and IgE, and antibodies from any subclass (eg, IgGl, IgG2, IgG3, and IgG4).
- the antibody may have a heavy chain constant region selected from, eg, IgGl, IgG2, IgG3, or IgG4.
- the antibody may also have a light chain selected from, for example, kappa ( ⁇ ) or lambda ( ⁇ ).
- the antibodies of the present application can be derived from any species.
- an antigen binding domain generally refers to a portion of an antibody molecule comprising the amino acids responsible for specific binding between the antibody and an antigen.
- the portion of an antigen that is specifically recognized and bound by an antibody is referred to as an "epitope" as described above.
- an antigen binding domain may typically comprise an antibody light chain variable region (VL) and an antibody heavy chain variable region (VH); however, it need not comprise both.
- Fd fragments for example, have two VH regions and generally retain some antigen-binding function of the intact antigen-binding domain.
- antigen-binding fragments of antibodies include (1) Fab fragments, monovalent fragments having VL, VH, constant light chain (CL) and CH1 domains; (2) F(ab')2 fragments, Bivalent fragment of two Fab fragments linked by a sulfur bridge; (3) Fd fragment with two VH and CH1 domains; (4) Fv fragment with VL and VH domains of the antibody one-arm, (5) dAb fragment (Ward et al., "Binding Activities of a Repertoire of Single Immunoglobulin Variable DomainsSecreted From Escherichia coli," Nature 341:544-546 (1989), which is incorporated by reference in its entirety), which has a VH domain; ( 6) Isolated Complementarity Determining Regions (CDRs); (7) Single-chain Fvs (scFvs), eg from scFV-libraries.
- Fab fragments monovalent fragments having VL, VH, constant light chain (CL) and CH
- the two domains of the Fv fragment, VL and VH are encoded by separate genes, they can be joined using recombinant methods by a synthetic linker that allows it to be prepared as a single protein in which the VL and VH domains are paired to form a monovalent molecule chain (referred to as single-chain Fv (scFv))
- scFv single-chain Fv
- Huston et al. "Protein Engineering of AntibodyBinding Sites: Recovery of Specific Activity in an Anti-Digoxin Single-ChainFv Analogue Produced in Escherichia coli," Proc. Natl. Acad . Sci.
- VHH relates to variable antigen binding domains of heavy chain antibodies from the family Camelidae (camelids, dromedaries, llamas, alpacas, etc.) (see Nguyen V.K. et al., 2000, The EMBO Journal, 19, 921-930; Muyldermans S., 2001, J Biotechnol., 74, 277-302 and review Vanlandschoot P. et al., 2011, Antiviral Research 92, 389-407) . VHHs may also be referred to as Nanobodies (Nb).
- variable region or “variable domain” generally refers to the domain of an antibody heavy or light chain that is involved in the binding of an antibody to an antigen.
- variable generally refers to certain portions of the sequence of the variable domains of antibodies that vary strongly, resulting in the binding and specificity of each particular antibody for its particular antigen. Variability is not evenly distributed throughout the variable region of an antibody. It is concentrated in three segments in the light and heavy chain variable regions, called complementarity determining regions (CDRs) or hypervariable regions (HVRs), LCDR1, LCDR2, LCDR3, HCDR1, HCDR2 and HCDR3. The more highly conserved portions of the variable domains are referred to as framework regions (FRs).
- CDRs complementarity determining regions
- HVRs hypervariable regions
- FRs framework regions
- variable domains of native heavy and light chains each comprise four FR regions (H-FR1, H-FR2, H-FR3, H-FR4, L-FR1, L-FR2, L-FR3, L-FR4) , mostly adopting a ⁇ -sheet configuration, connected by three loop regions of the CDR structure.
- the CDRs in each chain are brought together in close proximity by the FR regions, and together with the CDRs from the other chain form the antigen-binding site of the antibody.
- variable regions of an antibody or the CDRs of an antibody can be encoded by a variety of methods, such as the Kabat numbering scheme and definition rules based on sequence variability (see, Kabat et al., Protein Sequences in Immunology, 5.
- peptide linker generally refers to the amino acid sequence by which the amino acid sequences of different domains in the PD-L1/TGF ⁇ dual inhibitor of the present application are connected to each other.
- An essential technical feature of such a peptide linker is that the peptide linker does not contain any polymerization activity.
- Preferred amino acid residues for peptide linkers include Gly, Ser and Thr, and are characterized by a length of 5 to 25 amino acid residues.
- Suitable peptide linkers include those described in US Pat. Nos. 4,751,180 and 4,935,233 or WO88/09344.
- a preferred embodiment of the peptide linker is characterized by the amino acid sequence Gly-Gly-Gly-Gly - Ser, ie Gly4Ser, or a polymer thereof, ie (Gly4Ser)x, where x is an integer 1 or greater.
- peptide linkers including non-promoting secondary structure, are known in the art and described, for example, in Dall'Acqua et al. (Biochem. (1998) 37, 9266-9273), Cheadle et al. (Mol Immunol ( 1992) 29, 21-30) and Raag and Whitlow (FASEB (1995) 9(1), 73-80).
- Peptide linkers that also do not contribute to any secondary structure are preferred.
- the domains are provided in connection with each other, eg by genetic engineering, as described in the Examples.
- Methods for preparing fusion and operably linked bispecific single chain constructs and expressing them in mammalian cells or bacteria are well known in the art (e.g. WO99/54440 or Sambrook et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 2001).
- the terms "antagonist” and “inhibitor” are used interchangeably and generally refer to compounds that are capable of reducing or inhibiting the biological function of a target protein or polypeptide, such as reducing or inhibiting the activity or expression of the target protein or polypeptide or Pharmacy. Inhibitors need not completely eliminate the biological function of the target protein or polypeptide, and in some embodiments, reduce activity by at least 50%, 60%, 70%, 80%, 90%, 95%, or 99%. While some of the antagonists of the present application specifically interact with (eg, bind to) the target, they inhibit the biological activity of the target protein or polypeptide by interacting with other members of the signal transduction pathway that includes the target protein or polypeptide The compounds of are also specifically included in this definition. Non-limiting examples of biological activities that are inhibited by antagonists include those activities associated with the development, growth or spread of tumors or undesired immune responses manifested in autoimmune diseases.
- the term "effective amount” or “therapeutically effective amount” generally refers to an amount of a compound or pharmaceutical composition described herein sufficient to achieve the intended use described below, including but not limited to disease treatment .
- a therapeutically effective amount may vary according to: the intended application (in vivo or in vitro); or the subject being treated and the disease condition, eg, the subject's weight and age, the severity of the disease condition; the mode of administration, etc., which can be determined by one of ordinary skill in the art Personnel are easily identified.
- the term also applies to doses that will induce a specific response in target cells, such as platelet adhesion and/or cell migration.
- the specific dosage will vary depending on, for example, the specific compound chosen, the dosing regimen followed, whether it is administered in combination with other agents, the time of administration, the tissue to which it is administered, and the physical delivery system by which it is delivered.
- in vivo generally refers to an event that occurs in a subject.
- an in vitro assay generally refers to events that occur outside the body of a subject.
- an in vitro assay includes any assay performed outside the subject.
- In vitro assays include cell-based assays in which live or dead cells are employed.
- In vitro assays also include cell-free assays in which intact cells are not employed.
- combination therapy or “combination” generally refers to the use of more than one compound or agent to treat a particular disorder or condition.
- a PI3K inhibitor can be administered in combination with at least one additional therapeutic agent.
- “Combination” is not intended to imply that the other therapy and the PI3K inhibitor must be administered and/or formulated for delivery together, but such delivery methods are within the scope of this application.
- the PI3K inhibitor can be administered concurrently with one or more additional agents prior to (eg, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks, or 16 weeks) or after (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks , 6 weeks, 8 weeks, 12 weeks, or 16 weeks).
- additional agents eg., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks , 6 weeks, 8 weeks, 12 weeks, or 16 weeks.
- each therapeutic agent will be administered at a dose and/or on a schedule determined for that particular agent.
- the other therapeutic agents can be administered in a single composition or in separate compositions with the PI3K inhibitors provided herein.
- the present application also contemplates higher combinations, such as triple therapy of PI3K inhibitor + PD-L1 inhibitor + TGF ⁇ inhibitor.
- administering generally refers to introducing the drug combination into a subject's body by any route of introduction or delivery. Any method known to those of skill in the art for contacting cells, organs or tissues with the drug combination can be employed. Including, but not limited to, intraarterial, intranasal, intraperitoneal, intravenous, intramuscular, subcutaneous transdermal or oral.
- the daily dose may be divided into one, two or more doses in suitable form to be administered at one, two or more times during a certain period of time.
- the term "administering” includes administering to a subject two or more agents such that the agents and/or their metabolites are present in the subject at the same or substantially the same time.
- co-administration of a PI3K inhibitor with an additional anti-cancer agent refers to any administration of the two active agents, separate or together, Two of the active agents are administered as part of an appropriate dosage regimen aimed at obtaining the benefits of the combination therapy.
- the two active agents can be administered as part of the same pharmaceutical composition or in separate pharmaceutical compositions.
- the additional agent may be administered before, concurrently with, or after administration of the PI3K inhibitor, or some combination thereof.
- the additional agent may be administered before, concurrently with, or after each administration of the PI3K inhibitor, or some combination thereof, or at a relative level relative to the PI3K inhibitor
- the agents are administered at different intervals for treatment, or administered in a single dose prior to a course of treatment with a PI3K inhibitor, at any time during a course of treatment with a PI3K inhibitor, or after a course of treatment with a PI3K inhibitor.
- the first agent may be administered prior to administration of the second therapeutic agent (eg, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours) , 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks ago), substantially simultaneously or thereafter (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks , 8 weeks or 12 weeks later).
- the second therapeutic agent eg., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks , 8 weeks or 12 weeks later.
- monotherapy refers to the use of an agent alone (also referred to herein as alone) (eg, as a single compound or agent), eg, to treat the same indication without a second active ingredient disease, such as cancer.
- monotherapy includes the use of a PI3K inhibitor or a second agent alone to treat cancer.
- synergy or synergy refers to the beneficial effect of combining two or more agents, eg, in a pharmaceutical composition or in a method of treatment.
- one or more beneficial effects are achieved through the use of a PI3K inhibitor in combination with a second therapeutic agent described herein (eg, one or more second therapeutic agents).
- a synergistic effect refers to a lower dose of one or both agents required to achieve the effect.
- a combination may provide a selected effect, eg, a therapeutic effect, when at least one agent is administered at a lower dose than that required to achieve the same therapeutic effect when the agent is administered as a monotherapy.
- the combination of a PI3K inhibitor (eg, a PI3K inhibitor) and a second agent (as described herein) allows the PI3K inhibitor to achieve the same therapeutic effect as when the PI3K inhibitor is administered as monotherapy administered at lower doses as required.
- the synergistic effect reduces, prevents, delays or reduces the occurrence or likelihood of occurrence of one or more side effects, toxicity, resistance otherwise associated with administration of at least one of the agents.
- the synergistic effect reduces resistance to at least one of the agents (eg, a measure of resistance is reduced or the likelihood of developing resistance is reduced) or delays the development of resistance to at least one of the agents produce.
- the synergistic effect is a reduction in minimal residual disease (MRD).
- the combination of a PI3K inhibitor (eg, a PI3K inhibitor described herein) and a second agent (eg, a second agent described herein) is effective to reduce MRD in a subject, eg, low at levels previously measured in the subject (eg, levels measured prior to administration of the combination).
- the combination of a PI3K inhibitor and a second agent is effective to reduce MRD in a subject below levels observed during or after treatment with a monotherapy, eg, comprising a PI3K inhibitor or a second agent Monotherapy of any of the medicaments.
- the MRD is reduced below the level observed during treatment with a monotherapy comprising a PI3K inhibitor. In certain embodiments, the MRD is reduced below the level observed during treatment with a monotherapy comprising the second agent. In certain embodiments, the combination is effective to reduce the level of MRD to a preselected cutoff value (eg, 1 malignant cell in 100 normal cells, 1 malignant cell in 1000 normal cells, or 10,000 normal cells 1 malignant cell in cells, or 1 malignant cell in 100,000 normal cells) or less. In certain embodiments, the preselected cutoff value is 1 malignant cell in 1000 normal cells. In certain embodiments, the preselected cutoff value is 1 malignant cell in 100,000 normal cells.
- a preselected cutoff value eg, 1 malignant cell in 100 normal cells, 1 malignant cell in 1000 normal cells, or 10,000 normal cells 1 malignant cell in cells, or 1 malignant cell in 100,000 normal cells
- synergy refers to a PI3K inhibitor (eg, a PI3K inhibitor or a pharmaceutically acceptable form thereof) and a second therapeutic agent (eg, one or more additional therapeutic agents or a pharmaceutically acceptable form thereof)
- a PI3K inhibitor eg, a PI3K inhibitor or a pharmaceutically acceptable form thereof
- a second therapeutic agent eg, one or more additional therapeutic agents or a pharmaceutically acceptable form thereof
- pharmaceutically acceptable generally refers to one or more nontoxic substances that do not interfere with the effectiveness of the biological activity of the active ingredient.
- Such formulations may generally contain salts, buffers, preservatives, compatible carriers and optionally other therapeutic agents.
- “pharmaceutically acceptable forms” of compounds include, but are not limited to, pharmaceutically acceptable salts, hydrates, solvates, isomers, prodrugs, and isotopically labeled derivatives of the disclosed compounds.
- “pharmaceutically acceptable forms” include, but are not limited to, pharmaceutically acceptable salts, isomers, prodrugs, and isotopically labeled derivatives of the disclosed compounds.
- the term "pharmaceutically acceptable salt” generally refers to a salt suitable for use in contact with a subject's tissue without undue toxicity, irritation, allergic reaction, etc., within the scope of sound medical judgment, and with reasonable benefit / hazard ratios that match those salts.
- Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19.
- Pharmaceutically acceptable salts of the compounds provided herein include salts derived from suitable inorganic and organic acids and bases.
- non-toxic acid addition salts are with inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric and perchloric or organic acids such as acetic, oxalic, maleic, tartaric , citric acid, succinic acid or malonic acid), or by using other methods used in the art such as ion exchange.
- inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric and perchloric or organic acids
- acetic, oxalic, maleic, tartaric , citric acid, succinic acid or malonic acid such as ion exchange.
- salts include adipate, alginate, ascorbate, aspartate, besylate, besylate, benzoate, bisulfate, boric acid Salt, butyrate, camphorate, camphorsulfonate, citrate, cyclopentane propionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate enedioate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodate, 2-hydroxy-ethanesulfonate, lactobionate , lactate, laurate, lauryl sulfate, malate, maleate, malonate, mesylate, 2-naphthalenesulfonate, nicotinate, nitrate, oil acid salt, oxalate, palmitate, pamoate, pectate,
- organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid , citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc.
- Pharmaceutically acceptable salts derived from suitable bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
- Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like.
- Additional pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium and amine cations formed using counter ions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitric acid root, lower alkyl sulfonate and aryl sulfonate.
- Organic bases from which salts can be derived include, for example, primary, secondary and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, basic ion exchange resins, and the like, such as isopropylamine, Trimethylamine, diethylamine, triethylamine, tripropylamine and ethanolamine.
- the pharmaceutically acceptable base addition salt is selected from the group consisting of ammonium, potassium, sodium, calcium and magnesium salts.
- solvate generally refers to a compound that also includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces.
- a solvate can be a disclosed compound or a pharmaceutically acceptable salt thereof.
- the solvent is water
- the solvate is a "hydrate”.
- Pharmaceutically acceptable solvents and hydrates are, for example, complexes that may include 1 to about 100, or 1 to about 10, or 1 to about 2, about 3, or about 4 molecules of solvent or water . It is to be understood that the term “compound” in this application includes compounds and solvates of compounds, as well as mixtures thereof.
- prodrug generally refers to a compound that is transformed in vivo to yield the disclosed compound or a pharmaceutically acceptable form of the compound.
- a prodrug may be inactive when administered to a subject, but is converted to an active compound in vivo, eg, by hydrolysis (eg, in blood).
- prodrugs have improved physical and/or delivery properties over the parent compound.
- Prodrugs are typically designed to enhance pharmacological and/or pharmacokinetic-based properties relative to the parent compound.
- Prodrug compounds often offer the advantages of solubility, histocompatibility, or delayed release in mammalian organisms (see, eg, Bundgard, H., Design of Prodrugs (1985), pp.
- prodrugs may include, but are not limited to, their physical properties, such as increased water solubility over the parent compound for parenteral administration at physiological pH, or they may enhance absorption from the digestive tract, or they may enhance long-term storage of the drug stability.
- prodrug is also intended to include any covalently bonded carrier that releases the active compound in vivo when the prodrug is administered to a subject.
- Prodrugs of active compounds as described herein can be prepared by modifying groups present in the active compound in a manner that cleaves into the parent active compound in routine practice or in vivo.
- Prodrugs include compounds in which the hydroxyl, amino, or sulfhydryl groups are bonded to any group that, when a prodrug of the active compound is administered to a subject, cleaved to form a free hydroxyl, free amino, or free sulfhydryl group, respectively .
- prodrugs examples include, but are not limited to, acetate, formate, and benzoate derivatives of alcohols in the active compound or acetamide, formamide, and benzamide derivatives of amine functional groups, and the like.
- Other examples of prodrugs include compounds comprising -NO, -NO2, -ONO or -ONO2 moieties.
- Prodrugs can generally be prepared using well-known methods, as in Burger's Medicinal Chemistry and Drug Discovery, 172-178, 949-982 (Manfred E. Wolff ed., 5th ed., 1995) and Design of Prodrugs (H. Bundgaard ed., Elsevier, Those described in New York, 1985).
- the prodrug may comprise a pharmaceutically acceptable ester formed by replacing the hydrogen atom of the acid group with a group that Groups such as (C1-C8) alkyl, (C2-C12) acyloxymethyl, 1-(acyloxy)ethyl having 4 to 9 carbon atoms, 1-methyl having 5 to 10 carbon atoms yl-1-(acyloxy)-ethyl, alkoxycarbonyloxymethyl having 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having 4 to 7 carbon atoms , 1-methyl-1-(alkoxycarbonyloxy)ethyl having 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having 3 to 9 carbon atoms, 4 to 1-(N-(alkoxycarbonyl)amino)ethyl, 3-phthaloyl, 4-crotonyllactone
- a prodrug can be formed by replacing the hydrogen atom of the alcohol group with a group such as (C1-C6) Acyloxymethyl, 1-((C1-C6)acyloxy)ethyl, 1-methyl-1-((C1-C6)acyloxy)ethyl, (C1-C6)alkoxycarbonyl Oxymethyl, N-(C1-C6)alkoxycarbonylaminomethyl, succinyl, (C1-C6)acyl, ⁇ -amino(C1-C4)acyl, arylacyl and ⁇ -aminoacyl or ⁇ -aminoacyl- ⁇ -aminoacyl, wherein each ⁇ -aminoacyl is independently selected from naturally occurring L-amino acids, P(O)(OH)2, -P(O)(O(C1-C6)alkanes group) 2 and a sugar group (a group generated by
- the prodrug can be formed by replacing the hydrogen atom in the amine group with a group such as R-carbonyl, RO- Carbonyl, NRR'-carbonyl, where R and R' are each independently (C1-C10)alkyl, (C3-C7)cycloalkyl, benzyl, natural alpha-aminoacyl or natural alpha-aminoacyl-natural alpha -aminoacyl; -C(OH)C(O)OY1, where Y1 is H, (C1-C6)alkyl or benzyl; -C(OY2)Y3, where Y2 is (C1-C4)alkyl and Y3 is (C1-C6)alkyl, carboxy(C1-C6)alkyl, amino(C1-C4)alkyl or mono-N- or di-N,N-(C1-C6)alkylaminoalkyl;- C
- isomers generally refer to different compounds having the same molecular formula.
- Stepoisomer generally refers to isomers that differ only in the arrangement of the atoms in space.
- the term “isomer” includes any and all geometric and stereoisomers.
- isomers include geometric double bond cis and trans isomers, also known as E- and Z- isomers; R- and S- enantiomers; diastereomers, (d)-isomers and (l)-isomers, racemic mixtures thereof; and other mixtures thereof falling within the scope of the present disclosure.
- enantiomers generally refer to a pair of stereoisomers that are non-superimposable mirror images of each other.
- a 1:1 mixture of a pair of enantiomers is a “racemic” mixture.
- the term “( ⁇ )” is used to denote a racemic mixture.
- “Diastereomers” are stereoisomers that have at least two asymmetric atoms, but are not mirror images of each other. Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When the compounds are pure enantiomers, the stereochemistry at each chiral carbon can be designated by R or S.
- Resolved compounds of unknown absolute configuration can be assigned (+) or (-) depending on the direction (right or left) that they rotate plane polarized light at the wavelength of the sodium D line.
- Certain compounds described in this application contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined in terms of absolute stereochemistry, such as (R)- or (S)-.
- the chemical entities, pharmaceutical compositions and methods of the present application are intended to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures.
- Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, the compounds are intended to include both E and Z geometric isomers.
- enantiomeric purity generally refers to the relative amount of the presence of a particular enantiomer relative to another enantiomer, expressed as a percentage. For example, if a compound that may have an (R)- or (S)-isomeric configuration exists as a racemic mixture, then with respect to either the (R)- or (S)-isomer, the The enantiomeric purity was about 50%. If one conformational form of the compound is superior to the other, for example, 80% (S)- and 20% (R)-, the compound has an enantiopurity of 80 for the (S)-isomeric form %.
- the enantiomeric purity of a compound can be determined by a variety of means known in the art, including but not limited to chromatography using chiral supports, polarization measurement of polarized light rotation, using chiral shifting reagents (including but not limited to containing NMR spectroscopy of chiral complexes of lanthanides or Pirkle alcohols), or derivatization of compounds using chiral compounds such as Mosher acids followed by chromatography or NMR spectroscopy.
- tautomer generally refers to a type of isomer that includes migration from at least one form of hydrogen atom and at least one change in valence (eg, a single bond to a double bond). , triple bond to double bond or triple bond to single bond, or vice versa) resulting in two or more interconvertible compounds.
- Teautomerism includes protonation or protonation tautomerism, which is considered a subset of acid-base chemistry.
- Proton shift tautomerism or “proton shift tautomerism” involves the migration of protons with a concomitant change in bond order. The exact ratio of tautomers depends on a variety of factors, including temperature, solvent and pH.
- tautomers Chemical equilibrium of tautomers can be achieved when tautomerization is possible (eg, in solution).
- Tautomerism ie, reactions that provide tautomeric pairs
- Exemplary tautomers include, but are not limited to, keto-enol; amide-imide; lactam-lactam; enamine-imine; and enamine-(different) enamine tautomerism structure.
- keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers.
- tautomerism is phenol-ketone tautomerism.
- a specific example of phenol-ketone tautomerism is the interconversion of pyridin-4-ol and pyridin-4(1H)-one tautomers.
- structures depicted herein are also intended to include compounds that differ only by the presence of one or more isotopically enriched atoms. For example, except that hydrogen is replaced or enriched with deuterium or tritium at one or more atoms in the molecule, or carbon is replaced or enriched with13C or14C at one or more atoms in the molecule or 14 C, compounds having the structures of the present application are within the scope of this disclosure.
- the compounds of this application also include isotopically-labeled compounds, which are the same as those described in this application, except that one or more atoms are separated by an atomic mass or mass number that is different from the atomic mass or mass number usually found in nature different atoms instead.
- isotopes that may be added to the disclosed compounds include isotopes of hydrogen , carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2H, 3H , 13C , 14C , 15N , 18O , 17O , 31P , 32P , 35S , 18F and 36Cl .
- isotopically-labeled disclosed compounds are useful in compound and/or matrix tissue distribution analysis.
- Tritium (ie, 3 H) and carbon-14 (ie, 14 C) isotopes can allow for easy and detectable preparation.
- substitution with heavier isotopes such as deuterium (ie, 2 H) may provide certain therapeutic advantages (eg, increased in vivo half-life or reduced dosage requirements) due to greater metabolic stability.
- Isotopically labeled disclosed compounds can generally be prepared by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
- the application provides compounds that also contain unnatural proportions of atomic isotopes at one or more of the atoms that make up the compound. All isotopic variations disclosed in this application, whether radioactive or not, are included within the scope of this disclosure.
- pharmaceutically acceptable carrier or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents and absorption delaying agents agent, etc.
- pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents and absorption delaying agents agent, etc.
- the use of such media and agents for pharmaceutically active substances is well known in the art. Unless any conventional medium or agent is incompatible with the active ingredient, its use in the experimental compositions disclosed herein is contemplated. Supplementary active ingredients can also be incorporated into the pharmaceutical compositions.
- tumor generally refers to any neoplastic cell growth and proliferation, malignant or benign, as well as any precancerous and cancerous cells and tissues.
- neoplastic refers to any form of abnormally regulated or unregulated cell growth, malignant or benign, resulting in abnormal tissue growth.
- neoplastic cells include malignant and benign cells with abnormally regulated or unregulated cell growth.
- cancer cancer, “cancerous”, “cell proliferative disorder”, “proliferative disorder” and “tumor” are not mutually exclusive when referred to in this application.
- a tumor can refer to a physical mass containing a majority of cancer cells, eg, cells that display any of the cancers described herein.
- a tumor can be a solid tumor or a non-solid tumor (eg, hematological tumor, lymphoma).
- the term "solid tumor” generally refers to an abnormal tissue growth or mass that usually does not contain cysts or fluid areas. Solid tumors can be benign (noncancerous) or malignant (cancerous).
- the tumor may be a tumor with abnormal expression of PD-1 or PD-L1 in cells and tissues.
- the tumor may be a tumor with abnormal expression or activity of TGF ⁇ or TGF ⁇ R in cells and tissues.
- the tumor can be a tumor with abnormal expression or activity of PI3K in cells and tissues.
- the term “resistance” generally refers to when the cancer has a reduced response to treatment, eg, to the extent that the cancer does not respond to treatment.
- the cancer may be resistant at the start of treatment or it may develop resistance during treatment.
- a subject with cancer may have one or more mutations that render it resistant to treatment, or the subject may develop such mutations during treatment.
- the term “refractory” can refer to cancers that have proven ineffective with treatment (eg, chemotherapeutic drugs, biologics, and/or radiation therapy). Refractory cancer tumors can shrink, but not to the point where treatment is known to be effective. Often, however, tumors remain the same size (stable disease), or grow (progressive disease) as they were before treatment.
- treatment and “treating” generally refer to methods of obtaining beneficial or desired results, including but not limited to therapeutic benefit.
- Therapeutic benefit includes, but is not limited to, eradication, inhibition, reduction or amelioration of the underlying disorder being treated. Additionally, therapeutic benefit is achieved by eradicating inhibition, reduction or amelioration of one or more physiological symptoms associated with the underlying disorder, whereby improvement is observed in the patient, but the patient may still have the underlying disorder.
- prevention and preventing generally refer to methods of obtaining beneficial or desired results, including but not limited to preventive benefits.
- a pharmaceutical composition can be administered to a patient at risk of developing a particular disease or to a patient reporting one or more physical symptoms of a disease, even if the disease has not been diagnosed.
- the term "subject” or “patient” generally refers to a human (ie, male or female of any age group, eg, a pediatric subject (eg, infant, child, adolescent) or an adult subject (eg, young human, middle-aged or elderly)) and/or other primates (eg, cynomolgus monkeys, rhesus monkeys); mammals, including commercially related mammals such as cattle, pigs, horses, sheep, goats, cats and/or dogs; and/or birds, including commercially related birds such as chickens, ducks, geese, quail and/or turkeys.
- a human ie, male or female of any age group, eg, a pediatric subject (eg, infant, child, adolescent) or an adult subject (eg, young human, middle-aged or elderly)) and/or other primates (eg, cynomolgus monkeys, rhesus monkeys); mammals, including commercially related mammals such
- the term “about” or “approximately” generally refers to an acceptable error in a particular value determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term “about” or “approximately” generally refers to 1, 2, 3, or 4 standard deviations. In certain embodiments, the term “about” or “approximately” generally means 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5% of a given value or range , 4%, 3%, 2%, 1%, 0.5% or 0.05%.
- the term “comprising” or “comprising” generally refers to an open-ended form, and it should be understood that it may also contain other substances not mentioned.
- a drug combination comprising a phosphoinositide 3-kinase (PI3K) inhibitor and a second therapeutic agent, wherein the second therapeutic agent is an inhibitor of an immune checkpoint, a TGF ⁇ inhibitor, a dual function immune checkpoint/ TGF ⁇ inhibitors or combinations thereof.
- PI3K phosphoinositide 3-kinase
- “comprising” should be understood as containing other substances in addition to the phosphoinositide 3-kinase (PI3K) inhibitor and the second therapeutic agent.
- the application provides a pharmaceutical combination comprising a phosphoinositide 3-kinase (PI3K) inhibitor and a second therapeutic agent, wherein the second therapeutic agent is an immune checkpoint inhibitor, a TGF ⁇ inhibitor, a dual function Immune checkpoint/TGF ⁇ inhibitors or combinations thereof.
- PI3K phosphoinositide 3-kinase
- the inhibitor of the immune checkpoint may comprise an agent capable of blocking the interaction of programmed death 1 (PD-1) with programmed death ligand 1 (PD-L1).
- PD-1 programmed death 1
- PD-L1 programmed death ligand 1
- the inhibitor of the immune checkpoint may comprise an inhibitor of programmed death ligand 1 (PD-L1) and/or programmed death 1 (PD-1).
- an inhibitor of human PD-1 such as an inhibitor of human PD-L1.
- the inhibitor of the immune checkpoint may comprise an anti-PD-L1 antibody or an antigen-binding fragment thereof, or an anti-PD-1 antibody or an antigen-binding fragment thereof.
- the inhibitor of PD-1 or PD-L1 can be an antibody molecule against PD-1 or PD-L1.
- PD-1 or PD-L1 inhibitors can be administered alone or in combination with other immune checkpoint modulators, eg, in combination with inhibitors of LAG-3, TIM-3, or CTLA-4.
- the pharmaceutical combination may include:
- the inhibitor of the immune checkpoint can comprise nucleic acid (eg, dsRNA, siRNA or shRNA), polypeptide (eg, soluble ligand, antibody or antigen-binding fragment thereof, immunoadhesin, fusion proteins, oligopeptides and other molecules), or compounds.
- nucleic acid eg, dsRNA, siRNA or shRNA
- polypeptide eg, soluble ligand, antibody or antigen-binding fragment thereof, immunoadhesin, fusion proteins, oligopeptides and other molecules
- the antibody can be selected from the group consisting of human antibodies, humanized antibodies, chimeric antibodies, multispecific antibodies, monoclonal antibodies and polyclonal antibodies.
- the antigen-binding fragment can be selected from the group consisting of: Fab, Fab', F(ab') 2 , Fv, scFv, diabody, Fd, dAb, VHH, large antibody and complementarity determining region (CDR) fragments.
- the antibody or antigen-binding fragment thereof may comprise a heavy chain variable region (VH) comprising HCDR1, HCDR2 and HCDR3.
- VH heavy chain variable region
- the antibody or antigen-binding fragment thereof may or may not also comprise a CH1 domain.
- the antibody or antigen-binding fragment thereof may or may not also comprise CH2 and CH3 domains.
- the antibody or antigen-binding fragment thereof comprises the domain of VH-CH2-CH3.
- the antibody or antigen-binding fragment thereof may further comprise an antibody heavy chain constant region.
- the antibody heavy chain constant region may be a human antibody heavy chain constant region.
- the human antibody heavy chain constant region may be selected from constant regions derived from the group of IgGl, IgG2, IgG3, IgG4 and variants thereof.
- the antibody or antigen-binding fragment thereof may further comprise a light chain variable region comprising LCDR1, LCDR2, LCDR3.
- the antibody or antigen-binding fragment thereof may comprise a heavy chain variable region (VH), which may contain HCDRl, HCDR2, and HCDR3, and a light chain variable region, which may contain LCDRl, LCDR2, LCDR3.
- VH heavy chain variable region
- LCDRl LCDR2, LCDR3.
- the antibody or antigen-binding fragment thereof may further comprise a light chain constant region (CL).
- CL light chain constant region
- the antibody or antigen-binding fragment thereof may comprise a heavy chain comprising VH and CH1, and an antibody light chain comprising VL and CL.
- the antibody or antigen-binding fragment thereof may comprise a heavy chain comprising VH, CH1, CH2 and CH3, and an antibody light chain comprising VL and CL.
- the inhibitor of the immune checkpoint can be a PD-1/PD-L1 inhibitor.
- PD-1/PD-L1 inhibitors include, but are not limited to, US 7,488,802, US 7,943,743, US 8,008,449, US 8,168,757, US 8,217,149, US 8,609,089, US 2010/028330, US 2012/0114649, WO 2003/042 /156712, WO 2010/089411, WO 2010/036959, WO 2011/066342, WO 2011/159877, WO 2011/082400 and WO 2011/161699, all of which are incorporated herein by reference in their entirety.
- the checkpoint modulator can be a PD-1 inhibitor.
- the checkpoint modulator can be an anti-PD-1 antibody.
- the anti-PD-1 antibody can be nivolumab.
- Alternative names for nivolumab include MDX-1106, MDX-1106-04, ONO-4538, or BMS-936558, and the CAS Registry Number is: 946414-94-4.
- Nivolumab is a full-length human IgG4 monoclonal antibody that specifically blocks PD-1.
- Nivolumab (clone 5C4) and other human monoclonal antibodies that specifically bind to PD-1 are disclosed in US 8,008,449 and WO 2006/121168.
- the anti-PD-1 antibody can be Pembrolizumab.
- Pembrolizumab (trade name KEYTRUDA, formerly known as Lambrolizumab, also known as Merck 3745, MK-3475 or SCH-900475) is a humanized IgG4 monoclonal antibody that binds to PD-1.
- Pembrolizumab is disclosed, for example, in Hamid, O. et al. (2013) New England Journal of Medicine 369(2):134-44, WO 2009/114335, and US 8,354,509.
- the anti-PD-1 antibody can be pidilizumab.
- Pidilizumab (CT-011; CureTech) is a humanized IgG1k monoclonal antibody that binds to PD-1.
- Pidilizumab and other humanized anti-PD-1 monoclonal antibodies are disclosed in WO 2009/101611.
- Other anti-PD1 antibodies are disclosed in US 8,609,089, US 2010/028330 and/or US 2012/0114649.
- the anti-PD-1 antibody can be AMP-514 (Amplimmune).
- the PD-1 inhibitor can be an immunoadhesin (eg, comprising an extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region (eg, the Fc region of an immunoglobulin sequence) immunoadhesins).
- an immunoadhesin eg, comprising an extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region (eg, the Fc region of an immunoglobulin sequence) immunoadhesins).
- the checkpoint modulator is a PD-L1 inhibitor.
- the checkpoint modulator can be an anti-PD-L1 antibody or antigen-binding fragment thereof.
- PD-L1 antibody or antigen-binding fragment thereof can include any anti-PD-L1 antibody or antigen-binding fragment thereof described in the art.
- the anti-PD-L1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region of an antibody
- the heavy chain variable region comprises HCDR1, HCDR2, HCDR3, each of which is associated with the following molecules, respectively HCDR1, HCDR2, HCDR3 have at least about 80% (eg, about 85%, 90% or 95%) sequence identity to: Atezolizumab, Avelumab, BMS-936559, MPDL3280A (RG7446) or durvalumab (MEDI4736).
- the heavy chain variable regions have at least about 80% (eg, about 85%, 90% or 95%) sequence identity to the heavy chain variable regions of the following molecules, respectively: Atezolizumab, Avelumab, BMS-936559, MPDL3280A, or durvalumab.
- the anti-PD-L1 antibody or antigen-binding fragment thereof comprises a heavy chain of an antibody, wherein the heavy chain is at least about 80% (e.g., about 85%, e.g., about 85%, respectively,) 90% or 95%) sequence identity: Atezolizumab, Avelumab, BMS-936559, MPDL3280A, or durvalumab.
- the anti-PD-L1 antibody or antigen-binding fragment thereof further comprises a light chain variable region of an antibody, wherein the light chain variable region comprises LCDR1, LCDR2, LCDR3, each of which is associated with the following Molecules LCDR1, LCDR2, LCDR3 have at least about 80% (eg, about 85%, 90% or 95%) sequence identity to: Atezolizumab, Avelumab, BMS-936559, MPDL3280A or durvalumab.
- the anti-PD-L1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region of an antibody, wherein the heavy chain variable region comprises HCDR1, HCDR2, HCDR3, wherein the light chain can
- the variable region comprises LCDR1, LCDR2, LCDR3, each of which has at least about 80% (eg, about 85%, 90% or 95%) sequence identity to HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, LCDR3, respectively, of the following molecules: Atezolizumab, Avelumab, BMS-936559, MPDL3280A (RG7446) or durvalumab (MEDI4736).
- the light chain variable regions have at least about 80% (eg, about 85%, 90% or 95%) sequence identity to the light chain variable regions of atezolizumab, Avelumab, BMS-936559, MPDL3280A, or durvalumab.
- the anti-PD-L1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region of an antibody, each of which has at least about 80% (eg, about 85%, 90% or 95%) sequence identity: Atezolizumab, Avelumab, BMS-936559, MPDL3280A (RG7446) or durvalumab (MEDI4736).
- the anti-PD-L1 antibody or antigen-binding fragment thereof further comprises a light chain of an antibody, wherein the light chain is at least about 80% (eg, about 85%, respectively) the light chain of the following molecule , 90% or 95%) sequence identity: Atezolizumab, Avelumab, BMS-936559, MPDL3280A, or durvalumab.
- the anti-PD-L1 antibody or antigen-binding fragment thereof comprises heavy and light chains of an antibody that are each at least about 80% (eg, about 85%, 90% or 95%) sequence identity to: Atezolizumab, Avelumab, BMS-936559, MPDL3280A (RG7446) or durvalumab (MEDI4736).
- the anti-PD-L1 antibody or antigen-binding fragment thereof comprises: Atezolizumab, Avelumab, BMS-936559, MPDL3280A, or durvalumab, or an antigen-binding fragment thereof, or a variant or biosimilar thereof, or its combination.
- the anti-PD-L1 antibody may also be a commercially available or published PD-L1 antibody in the literature. Including but not limited to, such as PD-L1 antibody BMS-936559, MPDL3280A, MEDI4736, MSB0010718C (see US2014341917, US20130034559, US8779108) and the like.
- an anti-PD-L1 antibody is MDX-1105.
- MDX-1105 also known as BMS-936559, is an anti-PD-L1 antibody as described in WO 2007/005874.
- the anti-PD-L1 antibody is YW243.55.S70.
- the YW243.55.S70 antibody is an anti-PD-L1 antibody as described in WO 2010/077634.
- the heavy and light chain variable region sequences of YW243.55.S70 are also described in WO2010/077634.
- the anti-PD-L1 antibody is MDPL3280A (Genentech/Roche).
- MDPL3280A is a human Fc-optimized IgG1 monoclonal antibody that binds to PD-L1.
- Human monoclonal antibodies to MDPL3280A and other PD-L1 are described in US 7,943,743 and US 2012/0039906.
- the anti-PD-L1 antibody is Avelumab (MSB0010718C).
- MSB0010718C also known as A09-246-2; Merck Serono
- Other humanized anti-PD-L1 antibodies are disclosed in WO 2013/079174.
- the anti-PD-L1 antibody is durvalumab (CAS Number: 1428935-60-7).
- the anti-PD-L1 antibody is Atezolizumab (CAS Number: 1380723-44-3).
- the anti-PD-L1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region of an antibody
- the heavy chain variable region comprises one or more heavy chain selectable from the group consisting of Variable region CDRs (HCDRs): (a) HCDR1 having at least about 70% sequence identity to the amino acid sequence set forth in SEQ ID NO:1; (b) HCDR2 having at least about 70% sequence identity to SEQ ID NO:2 and (c) a HCDR3 having at least about 70% sequence identity to SEQ ID NO:3.
- HCDRs Variable region CDRs
- the anti-PD-L1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region of an antibody
- the heavy chain variable region comprises one or more HCDRs selected from the group consisting of: ( a) HCDR1 with the amino acid sequence shown in SEQ ID NO: 1 or HCDR1 obtained by amino acid addition, elimination or substitution reaction with no more than 2 amino acid differences from the amino acid sequence shown in SEQ ID NO: 1; (b) HCDR2 having the amino acid sequence shown in SEQ ID NO: 2 or HCDR2 obtained by amino acid addition, elimination or substitution reaction and having no more than 2 amino acid differences with the amino acid sequence shown in SEQ ID NO: 2; and (c) having The HCDR3 of the amino acid sequence shown in SEQ ID NO: 3 or the HCDR3 obtained by amino acid addition, elimination or substitution reaction with the amino acid sequence shown in SEQ ID NO: 3 differs by no more than 2 amino acids.
- the anti-PD-L1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region of an antibody
- the heavy chain variable region comprises HCDR1, HCDR2, HCDR3 comprising the
- the amino acid sequence set forth in ID NO: 1 is at least about 70% identical in sequence
- the HCDR2 comprises an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO: 2
- the HCDR3 comprises an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO: 2
- the anti-PD-L1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region of an antibody
- the heavy chain variable region comprises HCDR1, HCDR2, HCDR3, and the HCDR1 comprises SEQ ID
- the HCDR2 comprises SEQ ID NO: The amino acid sequence shown in: 2 or the amino acid sequence obtained by amino acid addition, elimination or substitution reaction with the amino acid sequence shown in SEQ ID NO: 2 with no more than 2 amino acid differences
- Described HCDR3 comprises SEQ ID NO: The amino acid sequence shown in 3 or the amino acid sequence obtained by amino acid addition, elimination or substitution reaction has no more than 2 amino acid differences with the amino acid sequence shown in SEQ ID NO: 3.
- the anti-PD-L1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region of an antibody
- the heavy chain variable region comprises an amino acid sequence selected from the group consisting of: (a) SEQ The amino acid sequence set forth in ID NO: 4; (b) an amino acid sequence at least about 85%, 90%, 95% or 99% identical to the amino acid sequence set forth in SEQ ID NO: 4; and (c) by adding The amino acid sequence obtained by the formation, elimination or substitution reaction with the amino acid sequence shown in SEQ ID NO: 4 has 1 or more differences.
- TGF ⁇ inhibitor binds TGF ⁇ 1, TGF ⁇ 2, or TGF ⁇ 3.
- the TGF[beta] inhibitor binds TGF[beta] or transforming growth factor beta receptor (TGF[beta]R).
- TGF[beta]R transforming growth factor beta receptor
- the TGF[beta] inhibitor can bind to TGF[beta] type I receptor (TGF[beta]RI), TGF[beta] type II receptor (TGF[beta]RII) or TGF[beta] type III receptor (TGF[beta]RIII).
- the TGF ⁇ inhibitor comprises: 1) an anti-TGF ⁇ antibody or antigen-binding fragment thereof; 2) an anti-TGF ⁇ R antibody or antigen-binding fragment thereof; 3) a small molecule TGF ⁇ inhibitor; 4) comprising transforming growth A protein of factor beta receptor II (TGF ⁇ RII) or a functionally active fragment thereof, or a variant or biosimilar thereof, or a combination thereof.
- TGF ⁇ RII transforming growth A protein of factor beta receptor II
- the anti-TGF ⁇ antibody or antigen-binding fragment thereof comprises a heavy chain variable region of an antibody, wherein the heavy chain variable region comprises HCDR1, HCDR2, HCDR3, each of which is associated with a Fresolimumab molecule (CAS), respectively.
- HCDR1, HCDR2, HCDR3 of Number: 948564-73-6 have at least about 80% (eg, about 85%, 90% or 95%) sequence identity.
- the heavy chain variable region can have at least about 80% (eg, about 85%, 90% or 95%) sequence identity to the heavy chain variable region of a Fresolimumab molecule.
- the heavy chain can have at least about 80% (eg, about 85%, 90% or 95%) sequence identity to the heavy chain of a Fresolimumab molecule.
- the anti-TGF ⁇ antibody or antigen-binding fragment thereof comprises a light chain variable region of an antibody
- the light chain variable region comprises LCDR1, LCDR2, LCDR3, each of which is associated with LCDR1 of a Fresolimumab molecule, respectively
- LCDR2, LCDR3 have at least about 80% (eg, 85%, 90% or 95%) sequence identity.
- the anti-TGF ⁇ antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region of an antibody, wherein the heavy chain variable region comprises HCDR1, HCDR2, HCDR3, wherein the light chain variable region Comprising LCDR1, LCDR2, LCDR3, each of which may have at least about 80% (eg, 85%, 90% or 95%) sequence identity to HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, LCDR3 of a Fresolimumab molecule, respectively.
- the light chain variable region can have at least about 80% sequence identity with the light chain variable region of a Fresolimumab molecule.
- the anti-TGF ⁇ antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region of an antibody, each of which may have at least about 80% of the heavy chain variable region and light chain variable region, respectively, of a Fresolimumab molecule. % (eg, about 85%, 90% or 95%) sequence identity.
- the light chain has at least about 80% sequence identity with the light chain of a Fresolimumab molecule.
- the anti-TGF ⁇ antibody or antigen-binding fragment thereof comprises heavy and light chains of the antibody, each of which may be at least about 80% (eg, 85%, 90%, or 95%), respectively, of the heavy and light chains of a Fresolimumab molecule. ) sequence identity.
- the anti-TGF ⁇ antibody or antigen-binding fragment thereof may comprise: Fresolimumab, or an antigen-binding fragment thereof, or a variant or biosimilar thereof.
- the small molecule TGF ⁇ inhibitor can include the following compounds: SB525334, SD-208, SB431542, LY2109761, LY2157299, GW788388, RepSox, SIS3, LDN-193189, EW-7197, LY364947, or the same combination.
- the TGF ⁇ RII can be a polypeptide having a wild-type human TGF ⁇ receptor type 2 isoform A sequence (eg, the amino acid sequence of NCBI Reference Sequence (Ref Seq) Accession No. NP_001020018), or a wild-type Polypeptides of human TGF ⁇ receptor type 2 isoform B sequence (e.g., the amino acid sequence of NCBI Ref Seq Accession No. NP_003233), or substantially identical (e.g., about 80%, 85%, 90%, or 95% identical to their amino acid sequence) sex) polypeptides.
- a wild-type human TGF ⁇ receptor type 2 isoform A sequence eg, the amino acid sequence of NCBI Reference Sequence (Ref Seq) Accession No. NP_001020018
- a wild-type Polypeptides of human TGF ⁇ receptor type 2 isoform B sequence e.g., the amino acid sequence of NCBI Ref Seq Accession No. NP_003233
- the functionally active fragment can comprise: human TGF ⁇ RII extracellular domain (ECD), any portion of NCBI Ref Seq Accession No. NP_001020018 or NCBI Ref Seq Accession No. NP_003233, or substantially identical to its amino acid sequence (e.g. , about 80%, 85%, 90% or 95% identical) sequences.
- ECD human TGF ⁇ RII extracellular domain
- TGF ⁇ RII or functionally active fragment thereof may comprise:
- (c) has an amino acid sequence with one or more amino acids added, deleted and/or substituted compared to the amino acid sequence shown in SEQ ID NO:6.
- bifunctional immune checkpoint/TGF ⁇ inhibitor is a fusion protein.
- the PD-L1/TGF ⁇ dual inhibitor or PD-1/TGF ⁇ dual inhibitor is a fusion protein.
- the dual PD-L1//TGF ⁇ inhibitor comprises a PD-L1 targeting moiety and a TGF ⁇ receptor domain comprising transforming growth factor beta receptor II (TGF ⁇ RII ) or a functionally active fragment thereof.
- TGF ⁇ RII transforming growth factor beta receptor II
- the dual PD-L1//TGF ⁇ inhibitor comprises a polypeptide
- the polypeptide comprises at least: (i) the heavy chain variable region of an anti-PD-L1 antibody; and (ii) TGF ⁇ RII or its functionally active fragments.
- the anti-PD-L1 antibody heavy chain variable region comprises HCDR1, HCDR2, HCDR3, and the HCDR1 comprises an amino acid sequence with at least 70% sequence identity to the amino acid sequence set forth in SEQ ID NO: 1
- the HCDR2 comprises an amino acid sequence having at least 70% sequence identity with the amino acid sequence shown in SEQ ID NO: 2
- the HCDR3 comprises an amino acid sequence having at least 70% sequence identity with the amino acid sequence shown in SEQ ID NO: 3.
- the anti-PD-L1 antibody heavy chain variable region comprises HCDR1, HCDR2, HCDR3, and the HCDR1 comprises the amino acid sequence shown in SEQ ID NO: 1 or by amino acid addition, elimination or substitution
- the amino acid sequence obtained by the reaction has no more than 2 amino acid differences with the amino acid sequence shown in SEQ ID NO: 1;
- the HCDR2 comprises the amino acid sequence shown in SEQ ID NO: 2 or through amino acid addition, elimination or substitution reaction
- the obtained amino acid sequence with the amino acid sequence shown in SEQ ID NO: 2 is no more than 2 amino acid differences;
- the HCDR3 comprises the amino acid sequence shown in SEQ ID NO: 3 or is obtained by amino acid addition, elimination or substitution reaction.
- the resulting amino acid sequence has no more than 2 amino acid differences with the amino acid sequence shown in SEQ ID NO: 3.
- the anti-PD-L1 antibody heavy chain variable region comprises an amino acid sequence selected from the group consisting of: (a) the amino acid sequence shown in SEQ ID NO: 4; (b) the same as SEQ ID NO: : an amino acid sequence with at least 85%, 90%, 95% or 99% sequence identity to the amino acid sequence shown in 4; Amino acid sequences have 1 or more differing amino acid sequences.
- TGF ⁇ RII or functionally active fragment thereof comprises:
- (c) has an amino acid sequence with one or more amino acids added, deleted and/or substituted compared to the amino acid sequence shown in SEQ ID NO:6.
- polypeptide further comprises a linker linking the C-terminus of the heavy chain variable region of the anti-PD-L1 antibody or antigen-binding fragment thereof to the TGF ⁇ RII or its function
- linker linking the C-terminus of the heavy chain variable region of the anti-PD-L1 antibody or antigen-binding fragment thereof to the TGF ⁇ RII or its function
- the N-termini of the active fragments are linked.
- the polypeptide further comprises CH2, CH3 domains, and the polypeptide comprises, from the N-terminus to the C-terminus, the heavy chain variable region (VH), CH2, CH3 domains and TGF ⁇ RII or its functionally active fragment, the C-terminus of the CH3 domain and the N-terminus of the TGF ⁇ RII or its functionally active fragment are connected by a linker.
- VH heavy chain variable region
- CH2, CH3 domains and TGF ⁇ RII or its functionally active fragment the C-terminus of the CH3 domain and the N-terminus of the TGF ⁇ RII or its functionally active fragment are connected by a linker.
- CH2 domains are derived from IgG.
- linker is a peptide linker
- amino acid sequence of the peptide linker is G( G4S ) x , wherein x is 3-6.
- the peptide linker comprises an amino acid sequence selected from the group consisting of: (a) the amino acid sequence set forth in SEQ ID NO:5; (b) having the amino acid sequence set forth in SEQ ID NO:5 An amino acid sequence having at least 85%, 90%, 95% or 99% sequence identity; and (c) an amino acid sequence obtained by addition, elimination or substitution reaction with 1 or more amino acid sequences shown in SEQ ID NO:5 Multiple differential amino acid sequences.
- polypeptide comprises an amino acid sequence selected from the group consisting of: (a) the amino acid sequence set forth in SEQ ID NO:7; (b) having at least the amino acid sequence set forth in SEQ ID NO:7 An amino acid sequence of 85%, 90%, 95% or 99% sequence identity; (c) the amino acid sequence obtained by addition, elimination or substitution reaction has 1 or more differences with the amino acid sequence shown in SEQ ID NO: 7 amino acid sequence.
- the PD-L1//TGF ⁇ dual inhibitor comprises two of the aforementioned polypeptides.
- the dual PD-L1/TGF ⁇ inhibitor comprises a first polypeptide and a second polypeptide
- the first polypeptide comprises at least: (i) the heavy chain of an anti-PD-L1 antibody and (ii) TGF ⁇ RII or a functionally active fragment thereof
- the second polypeptide comprises at least the light chain variable region of an anti-PD-L1 antibody
- the heavy chain variable region of the first polypeptide and The light chain variable regions of the second polypeptide are capable of specifically binding PD-L1 when combined.
- the first polypeptide further comprises a linker that connects the C-terminus of the heavy chain variable region of the anti-PD-L1 antibody or antigen-binding fragment thereof to the TGF ⁇ RII or the N-terminus of a functionally active fragment thereof.
- the dual PD-L1/TGF ⁇ inhibitor comprises a first polypeptide and a second polypeptide, wherein:
- the first polypeptide sequentially comprises the heavy chain variable region (VH) of the anti-PD-L1 antibody, the CH1 domain, and TGF ⁇ RII or a functionally active fragment thereof from the N-terminus to the C-terminus, and the C-terminus of the CH1 domain is related to the The N-terminus of the TGF ⁇ RII or its functionally active fragment is connected by a linker; and the second polypeptide comprises a light chain variable region (VL) and a light chain constant region (CL) of an anti-PD-L1 antibody from the N-terminus to the C-terminus ).
- the dual PD-L1/TGF ⁇ inhibitor comprises a first polypeptide and a second polypeptide, wherein:
- the first polypeptide comprises the heavy chain variable region (VH), CH1, CH2, CH3 domains of the anti-PD-L1 antibody and TGF ⁇ RII or a functionally active fragment thereof in sequence from the N-terminus to the C-terminus, and the CH3 domain is The C-terminus is connected with the N-terminus of the TGF ⁇ RII or its functionally active fragment through a linker; and the second polypeptide comprises the light chain variable region (VL), light chain of an anti-PD-L1 antibody from the N-terminus to the C-terminus Constant region (CL).
- VH heavy chain variable region
- linker is a peptide linker
- the first polypeptide has at least about 80% sequence identity to a functionally identical polypeptide of M7824 or SHR-1701.
- the second polypeptide has at least about 80% sequence identity to a functionally identical polypeptide of M7824 or SHR-1701.
- the dual PD-L1/TGF ⁇ inhibitor comprises M7824, SHR-1701, or a variant or biosimilar thereof, or a combination thereof.
- a PI3K inhibitor can be a compound that inhibits one or more PI3K isoforms, eg, alpha, beta, delta, or gamma isoforms.
- the PI3K inhibitor can be a compound that inhibits the alpha, beta, delta and gamma isoforms of PI3K.
- the PI3K inhibitor can be a compound that inhibits the beta, delta, and gamma isoforms of PI3K.
- the PI3K inhibitor may be a compound that inhibits the delta and gamma isoforms of PI3K, ie, a dual PI3K delta/gamma inhibitor.
- the PI3K inhibitor can comprise a compound of formula (IA-I), (IA-II), (IA-III), or (IA-IV):
- R can be independently selected from hydrogen, halogen, -OR a , CN, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-8 cycloalkyl and substituted or unsubstituted heterocyclic groups;
- Cy 1 may be selected from substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted 3- to 15-membered heterocyclic group having at least one heteroatom selected from N, O and S , substituted or unsubstituted C6-20 aryl and substituted or unsubstituted monocyclic groups of 5- to 14-membered heteroaryl groups having one or more heteroatoms selected from N, O and S;
- Each occurrence of R a may be the same or different and independently selected from hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted C 1-6 alkyl; -NR c R d , where R c , R d independently selected from hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted C1-6 alkyl and C1-6 alkoxy, and -ORc , wherein Rc is substituted or unsubstituted C 1-6 alkyl;
- n may be an integer from 1-4;
- q can be 0, 1 or 2;
- Each occurrence of X can be independently selected from CR 3 or N;
- R can be independently selected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1- 8 alkoxy, substituted or unsubstituted C 2-10 alkenyl, substituted or unsubstituted C 2-12 alkynyl, substituted or unsubstituted C 6-20 aryl, substituted or unsubstituted Unsubstituted C 6-20 aryl C 1-8 alkyl, substituted or unsubstituted C 3-20 cycloalkyl, substituted or unsubstituted C 3-20 cycloalkyl C 1-8 Alkyl, substituted or unsubstituted C 3-8 cycloalkenyl C 1-8 alkyl, substituted or unsubstituted C 3-8 cycloalkenyl, substituted or unsubstituted with one or more 5- to 14-membered heteroaryl
- guanidine, -COORx , -C(O)Rx, -C(S) Rx , -C(O ) NRxRy , -C (O ) ONRxRy , - NR y R z , -NR x CONR y R z , -N(R x )SOR y , -N(Rx)SO 2 R y , -( NN(R x )R y ), -NR x C(O ) ORy , -NRxRy , -NRxC ( O) Ry -,- NRxC ( S) Ry , -NRxC ( S) NRyRz , -SONRxRy- , -SO 2 NR x R y -, -OR x , -OR x C(O)NR y R z , -OR x C(O)OR y
- the PI3K inhibitor can include a compound of formula (IA-V):
- R can be independently selected from hydrogen, halogen, -OR a , CN, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-8 cycloalkyl and substituted or unsubstituted heterocyclic groups;
- a saturated 3-10 membered ring including carbon atoms bound to R and R, the ring may optionally include one or more heteroatoms that are the same or different and selected from O, NR a and S;
- Each occurrence of X can be independently selected from CR 3 or N;
- Each occurrence of R can be independently selected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 Alkoxy, substituted or unsubstituted C 2-10 alkenyl, substituted or unsubstituted C 2-12 alkynyl, substituted or unsubstituted C 6-20 aryl, substituted or unsubstituted Substituted C 6-20 aryl C 1-8 alkyl, substituted or unsubstituted C 3-20 cycloalkyl, substituted or unsubstituted C 3-20 cycloalkyl C 1-8 alkane base, substituted or unsubstituted C 3-8 cycloalkenyl C 1-8 alkyl, substituted or unsubstituted C 3-8 cycloalkenyl, substituted or unsubstituted with one or more 5- to 14-membered heteroaryl
- R 5 can be hydrogen, C 1-6 alkyl or halogen
- n can be 0, 1, 2, 3, or 4; and p can be 0, 1, 2, 3, 4, or 5.
- the PI3K inhibitor can include a compound of formula (IA-VI):
- R can be independently selected from hydrogen, halogen, -OR a , CN, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-8 cycloalkyl and substituted or unsubstituted heterocyclic groups;
- Each occurrence of X can be independently selected from CR 3 or N;
- Each occurrence of R can be independently selected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 Alkoxy, substituted or unsubstituted C 2-10 alkenyl, substituted or unsubstituted C 2-12 alkynyl, substituted or unsubstituted C 6-20 aryl, substituted or unsubstituted Substituted C 6-20 aryl C 1-8 alkyl, substituted or unsubstituted C 3-20 cycloalkyl, substituted or unsubstituted C 3-20 cycloalkyl C 1-8 alkane base, substituted or unsubstituted C 3-8 cycloalkenyl C 1-8 alkyl, substituted or unsubstituted C 3-8 cycloalkenyl, substituted or unsubstituted with one or more 5- to 14-membered heteroaryl
- R 5 can be hydrogen, C 1-6 alkyl or halogen
- n can be 0, 1, 2, 3 or 4;
- P can be 0, 1, 2, 3, 4 or 5.
- R can be hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, or OR a , for another example, wherein R a can be alkyl.
- Cy 1 can be selected from:
- R 1 and R 2 may each independently represent hydrogen or substituted or unsubstituted C 1-6 alkyl.
- R3 can be iodo, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted Substituted heteroaryl.
- R 3 can be hydrogen, halogen, hydroxy, or NH 2 , as another example, wherein said R 3 can be hydrogen.
- the PI3K inhibitor can include:
- the PI3K inhibitor may comprise: 2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromene-4 - Ketones, or their enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers, or isotopic variants; or pharmaceutically acceptable salts, solvates thereof , hydrate or prodrug.
- the PI3K inhibitor may be (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chrome En-4-one (Tenalisib, also known as CN401) or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.
- the pharmaceutical combination may include an anti-PD-L1 antibody or antigen-binding fragment thereof and a PI3K inhibitor.
- the pharmaceutical combination may include: (i) an anti-PD-L1 antibody or antigen-binding fragment thereof comprising Atezolizumab, Avelumab, BMS-936559, MPDL3280A or durvalumab or an antigen thereof Binding fragments; (ii) dual PI3K ⁇ / ⁇ inhibitors including 2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl) -4H-chromen-4-one, or an enantiomer, mixture of enantiomers, mixture of two or more diastereomers, or isotopic variant thereof; or a pharmaceutically acceptable variant thereof Acceptable salts, solvates, hydrates or prodrugs.
- an anti-PD-L1 antibody or antigen-binding fragment thereof comprising Atezolizumab, Avelumab, BMS-936559, MPDL3280A or durvalumab or an antigen thereof Binding fragments
- the pharmaceutical combination can include: (i) an anti-PD-L1 antibody selected from the group consisting of Atezolizumab, Avelumab, BMS-936559, MPDL3280A, durvalumab, or a combination thereof; (ii) (S)-2-(1 -(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof .
- the pharmaceutical combination may include a TGF ⁇ inhibitor and a PI3K inhibitor.
- the pharmaceutical combination may include: (i) a TGF ⁇ inhibitor comprising: an anti-TGF ⁇ antibody or antigen-binding fragment thereof, a small molecule TGF ⁇ inhibitor or a combination thereof, the TGF ⁇ antibody or antigen-binding fragment thereof Including Fresolimumab or an antigen-binding fragment thereof, the small molecule TGF ⁇ inhibitor includes SB525334, SD-208, SB431542, LY2109761, LY2157299 (Galunisertib), GW788388, RepSox, SIS3, LDN-193189, EW-7197, LY364947 or a combination thereof; (ii) dual PI3K ⁇ / ⁇ inhibitors comprising 2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H- A chromen-4-one, or an enantiomer, mixture of enantiomers, mixture of two or more diastereomers, or isotopic variant thereof; or
- the pharmaceutical combination may include: Fresolimumab or an antigen-binding fragment thereof and (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)- 4H-chromen-4-one or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.
- the pharmaceutical combination may include: Fresolimumab or an antigen-binding fragment thereof, SB431542, and (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl) )-4H-chromen-4-one or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.
- the pharmaceutical combination may include the PD-1 inhibitor, the TGF ⁇ inhibitor, and the PI3K inhibitor.
- the pharmaceutical combination may include: (i) an anti-PD-1 antibody or antigen-binding fragment thereof, the anti-PD-1 antibody or antigen-binding fragment thereof including nivolumab, pembrolizumab, pidilizumab Anti- or AMP-514 or an antigen-binding fragment thereof; (ii) a dual PI3K ⁇ / ⁇ inhibitor comprising 2-(1-(9H-purin-6-ylamino)propyl)-3 -(3-Fluorophenyl)-4H-chromen-4-one, or its enantiomer, mixture of enantiomers, mixture of two or more diastereomers, or Isotopic variants; or pharmaceutically acceptable salts, solvates, hydrates or prodrugs thereof; (iii) anti-TGF ⁇ antibodies or antigen-binding fragments thereof, small molecule TGF ⁇ inhibitors or combinations thereof, said TGF ⁇ antibodies or antigens thereof Binding fragments include Fresolimumab or an anti-
- the pharmaceutical combination can include: (i) an anti-PD-1 antibody selected from the group consisting of nivolumab, pembrolizumab, pidilizumab, or AMP-514, or a combination thereof; (ii) (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one or a pharmaceutically acceptable salt thereof, A solvate, hydrate or prodrug; (iii) Fresolimumab or an antigen-binding fragment thereof and/or SB431542.
- the pharmaceutical combination may include the PD-L1 inhibitor, the TGF ⁇ inhibitor, and the PI3K inhibitor.
- the pharmaceutical combination may include: (i) an anti-PD-L1 antibody or antigen-binding fragment thereof comprising Atezolizumab, Avelumab, BMS-936559, MPDL3280A or durvalumab or an antigen thereof Binding fragments; (ii) dual PI3K ⁇ / ⁇ inhibitors including 2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl) -4H-chromen-4-one, or an enantiomer, mixture of enantiomers, mixture of two or more diastereomers, or isotopic variant thereof; or a pharmaceutically acceptable variant thereof acceptable salts, solvates, hydrates or prodrugs; (iii) anti-TGF ⁇ antibodies or antigen-binding fragments thereof including Fresolimumab or antigen-binding fragments thereof.
- the pharmaceutical combination may include: (i) an anti-PD-L1 antibody selected from the group consisting of Atezolizumab, Avelumab, BMS-936559, MPDL3280A, or durvalumab, or a combination thereof; (ii) (S)-2-(1 -(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof ; (iii) Fresolimumab or an antigen-binding fragment thereof.
- an anti-PD-L1 antibody selected from the group consisting of Atezolizumab, Avelumab, BMS-936559, MPDL3280A, or durvalumab, or a combination thereof.
- the pharmaceutical combination may include the dual PD-L1/TGF ⁇ inhibitor and a PI3K inhibitor.
- the PD-L1/TGF ⁇ dual inhibitor may be those described in PCT/CN2019124535, the entire contents of which are incorporated herein by reference.
- the dual PD-L1/TGF ⁇ inhibitor can be WBP1126 (also known as CN202), or a variant or biosimilar thereof.
- the WBP1126 can comprise two polypeptides, the polypeptides from the N-terminus to the C-terminus sequentially comprise the heavy chain variable region (VH), CH2, CH3 domains of an anti-PD-L1 antibody, and TGF ⁇ RII or a functionally active fragment thereof, the The C-terminus of the CH3 domain is connected to the N-terminus of the TGF ⁇ RII or its functionally active fragment through a linker; for example, the polypeptide may have the amino acid sequence shown in Table 1:
- the dual PD-L1/TGF ⁇ inhibitor comprises a first polypeptide and a second polypeptide
- the first polypeptide comprises at least: (i) the heavy chain of an anti-PD-L1 antibody and (ii) TGF ⁇ RII or a functionally active fragment thereof
- the second polypeptide comprises at least the light chain variable region of an anti-PD-L1 antibody
- the heavy chain variable region of the first polypeptide and The light chain variable regions of the second polypeptide are capable of specifically binding PD-L1 when combined.
- the dual PD-L1/TGF ⁇ inhibitor further comprises a linker connecting the C-terminus of the heavy chain variable region of the anti-PD-L1 antibody or antigen-binding fragment thereof linked to the N-terminus of the TGF ⁇ RII or its functionally active fragment.
- the dual PD-L1/TGF ⁇ inhibitor comprises a first polypeptide and a second polypeptide, wherein:
- the first polypeptide sequentially comprises the heavy chain variable region (VH) of the anti-PD-L1 antibody, the CH1 domain, and TGF ⁇ RII or its functionally active fragment from the N-terminus to the C-terminus, and the C-terminus of the CH1 domain is related to the The N-terminus of the TGF ⁇ RII or its functionally active fragment is connected by a linker; and the second polypeptide comprises a light chain variable region (VL) and a light chain constant region (CL) of an anti-PD-L1 antibody from the N-terminus to the C-terminus ).
- the dual PD-L1/TGF ⁇ inhibitor comprises a first polypeptide and a second polypeptide, wherein:
- the first polypeptide comprises the heavy chain variable region (VH), CH1, CH2, CH3 domains of the anti-PD-L1 antibody and TGF ⁇ RII or its functionally active fragments in sequence from the N-terminus to the C-terminus, and the CH3 domain is The C-terminus is connected with the N-terminus of the TGF ⁇ RII or its functionally active fragment through a linker; and the second polypeptide comprises the light chain variable region (VL), light chain of an anti-PD-L1 antibody from the N-terminus to the C-terminus Constant region (CL).
- VH heavy chain variable region
- CH1, CH2, CH3 domains of the anti-PD-L1 antibody and TGF ⁇ RII or its functionally active fragments in sequence from the N-terminus to the C-terminus
- the CH3 domain is The C-terminus is connected with the N-terminus of the TGF ⁇ RII or its functionally active fragment through a linker
- the second polypeptide comprises the light chain variable region (VL), light chain
- linker is a peptide linker
- the first polypeptide of the dual PD-L1/TGF ⁇ inhibitor may have at least about 80% sequence identity to a functionally identical polypeptide of M7824 or SHR-1701.
- the second polypeptide of the dual PD-L1/TGF ⁇ inhibitor may have at least about 80% sequence identity to a functionally identical polypeptide of M7824 or SHR-1701.
- the PD-L1/TGF ⁇ dual inhibitor may be those described in PCT/EP2015052781, PCT/CN2018086451, all of which are incorporated herein by reference in their entirety.
- the PD-L1/TGF ⁇ dual inhibitor can be selected from M7824, SHR-1701, or variants or biosimilars thereof, or a combination thereof.
- the dual PD-L1/TGF ⁇ inhibitor and the PI3K inhibitor may not be mixed with each other in the pharmaceutical combination.
- the dual PD-L1/TGF ⁇ inhibitor and the PI3K inhibitor can each be independently present in separate containers.
- the present application provides a pharmaceutical composition
- a pharmaceutical composition comprising the aforementioned PI3K inhibitor and a second therapeutic agent, and optionally one or more pharmaceutically acceptable carriers or excipients.
- the second therapeutic agent is the aforementioned dual PD-L1/TGF ⁇ inhibitor.
- the PI3K inhibitor is the aforementioned dual PI3K delta/gamma inhibitor.
- the pharmaceutical composition includes a dual PD-L1/TGF ⁇ inhibitor and a PI3K ⁇ / ⁇ dual inhibitor.
- the pharmaceutical composition may comprise: i) WBP1126 or a variant or biosimilar thereof;
- the second therapeutic agent is the aforementioned anti-PD-L1 antibody
- the PI3K inhibitor is the aforementioned dual PI3K ⁇ / ⁇ inhibitor.
- the pharmaceutical composition may include: i) nivolumab, pembrolizumab, pidilizumab, or a combination thereof; and ii) Tenalisib or a pharmaceutically acceptable salt, solvate, hydrate thereof or prodrugs.
- the second therapeutic agent is the aforementioned dual PD-L1/TGF ⁇ inhibitor
- the PI3K inhibitor is a PI3K ⁇ inhibitor
- the pharmaceutical composition may comprise: i) WBP1126 or a variant or biosimilar thereof;
- Alplisib or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.
- the second therapeutic agent and the PI3K inhibitor are present in a single or separate dosage form.
- per unit dosage form comprises a dose of 1-1000 mg of the first therapeutic agent, such as a PI3K inhibitor active substance (eg CN401 (Tenalisib)), For example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 40, 50, 60 , 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1000mg or a value between any two of the above; and, each unit dosage form (unit dosage form) contains a second therapeutic agent in a dose of 1-1000 mg, such as a PD-L1 inhibitor, a TGF ⁇ inhibitor, a PD-L1 inhibitor, Any one of PD-L1/TGF ⁇ dual inhibitor (eg CN202 (WBP1126)) or PD-1/TGF ⁇ dual inhibitor or combination thereof, eg 1,
- a PI3K inhibitor active substance eg CN
- the pharmaceutical combinations of the present application may be used in combination or in combination with one or more third active substances or therapies useful in the treatment, prevention or amelioration of a proliferative disorder, disease or condition.
- the drug combinations of the present application are administered in combination with any conventional anti-tumor therapy including, but not limited to, immunotherapy, therapeutic antibodies, targeted therapy, surgery, radiation therapy, or chemotherapy.
- the active substance may be a chemotherapeutic drug, for example, an alkylating agent, an antimetabolite, an anthracycline, a plant alkaloid, a topoisomerase inhibitor, an antineoplastic antibiotic, a hormonal drug, an antiangiogenic agent, a differentiation inducer , cell growth arrest inducers, apoptosis inducers, cytotoxic drugs and other antitumor drugs.
- chemotherapeutic drug for example, an alkylating agent, an antimetabolite, an anthracycline, a plant alkaloid, a topoisomerase inhibitor, an antineoplastic antibiotic, a hormonal drug, an antiangiogenic agent, a differentiation inducer , cell growth arrest inducers, apoptosis inducers, cytotoxic drugs and other antitumor drugs.
- chemotherapeutic drug for example, an alkylating agent, an antimetabolite, an anthracycline, a plant alkaloid, a top
- chemotherapeutic agents include, but are not limited to, alkylating agents (eg, cisplatin, carboplatin, oxaliplatin, dichloromethyldiethylamine, cyclophosphamide, chlorambucil, dacarbazine, lolimus) pyridoxine, carmustine, procarbazine, chlorambucil, and ifosfamide), antimetabolites (eg, fluorouracil (5-FU), gemcitabine, methotrexate, cytarabine, fludara pyridine and fluorouracil), antimitotics (including taxanes (such as paclitaxel and docetaxel) and vinca alkaloids (such as vinblastine, vincristine, vinblastine, vinorelbine, and vinblastine) Desine), anthracyclines (including doxorubicin, daunorubicin, valrubicin, idarubicin, and epirubicin, and
- the third active substance can be selected from vincristine, vinblastine, vindesine, etoposide, docetaxel, paclitaxel, irinotecan, vinorelbine, mitoxantrone , any one of vinflunine and topotecan or any combination thereof.
- third therapies that can be used in conjunction with the methods provided herein include, but are not limited to, surgery, radiation therapy, endocrine therapy, biological response modifiers (eg, interferons, interleukins, and tumor necrosis factor (TNF)) , hyperthermia and cryotherapy, and medications to reduce any adverse effects (eg, antiemetics).
- biological response modifiers eg, interferons, interleukins, and tumor necrosis factor (TNF)
- hyperthermia and cryotherapy e.g, hyperthermia and cryotherapy
- medications to reduce any adverse effects eg, antiemetics.
- the present application provides a method for treating and/or preventing tumors, comprising administering to a subject in need thereof: an effective amount of the aforementioned pharmaceutical combination, or the aforementioned pharmaceutical composition.
- the method comprises administering to a subject in need thereof: an effective amount of the aforementioned PI3K inhibitor and the aforementioned inhibitor of immune checkpoints. In certain embodiments, the method comprises administering to a subject in need thereof: an effective amount of the aforementioned PI3K inhibitor and the aforementioned TGF ⁇ inhibitor. In certain embodiments, the method comprises administering to a subject in need thereof: an effective amount of the aforementioned PI3K inhibitor, the aforementioned TGF ⁇ inhibitor, and the aforementioned inhibitor of immune checkpoints.
- the method can comprise administering to a subject in need thereof: an effective amount of the aforementioned PI3K inhibitor, such as the aforementioned (S)-2-(1-(9H-purin-6-ylamino)propyl) -3-(3-fluorophenyl)-4H-chromen-4-one or a pharmaceutically acceptable salt thereof and the aforementioned anti-PD-L1 antibody, for example, Atezolizumab, Avelumab, BMS-936559, MPDL3280A, durvalumab, or their combination.
- the aforementioned PI3K inhibitor such as the aforementioned (S)-2-(1-(9H-purin-6-ylamino)propyl) -3-(3-fluorophenyl)-4H-chromen-4-one or a pharmaceutically acceptable salt thereof
- the aforementioned anti-PD-L1 antibody for example, Atezolizumab, Avelumab, BMS-936559, MPDL3280A, durvalumab
- the method can comprise administering to a subject in need thereof: an effective amount of the aforementioned PI3K inhibitor, such as the aforementioned (S)-2-(1-(9H-purin-6-ylamino)propyl) -3-(3-Fluorophenyl)-4H-chromen-4-one or a pharmaceutically acceptable salt thereof and the aforementioned TGF ⁇ inhibitor, eg, Fresolimumab, SB525334 or a combination thereof.
- the aforementioned PI3K inhibitor such as the aforementioned (S)-2-(1-(9H-purin-6-ylamino)propyl) -3-(3-Fluorophenyl)-4H-chromen-4-one or a pharmaceutically acceptable salt thereof
- the aforementioned TGF ⁇ inhibitor eg, Fresolimumab, SB525334 or a combination thereof.
- the method can comprise administering to a subject in need thereof: an effective amount of the aforementioned PI3K inhibitor, such as the aforementioned (S)-2-(1-(9H-purin-6-ylamino)propyl) -3-(3-Fluorophenyl)-4H-chromen-4-one or a pharmaceutically acceptable salt thereof; the aforementioned TGF ⁇ inhibitors, eg, Fresolimumab, SB525334 or a combination thereof; the aforementioned anti-PD-L1 Antibodies, eg, Atezolizumab, Avelumab, BMS-936559, MPDL3280A, durvalumab, or a combination thereof.
- the aforementioned PI3K inhibitor such as the aforementioned (S)-2-(1-(9H-purin-6-ylamino)propyl) -3-(3-Fluorophenyl)-4H-chromen-4-one or a pharmaceutically acceptable salt thereof
- the method can comprise administering to a subject in need thereof: an effective amount of the aforementioned PI3K inhibitor, such as the aforementioned (S)-2-(1-(9H-purin-6-ylamino)propyl) -3-(3-fluorophenyl)-4H-chromen-4-one or a pharmaceutically acceptable salt thereof; the aforementioned TGF ⁇ inhibitors, eg, Fresolimumab, SB525334 or a combination thereof; the aforementioned anti-PD-1 Antibodies, eg, nivolumab, pembrolizumab, pidilizumab, or a combination thereof.
- the aforementioned PI3K inhibitor such as the aforementioned (S)-2-(1-(9H-purin-6-ylamino)propyl) -3-(3-fluorophenyl)-4H-chromen-4-one or a pharmaceutically acceptable salt thereof
- the aforementioned TGF ⁇ inhibitors eg, Fresolim
- the method comprises administering to a subject in need thereof: an effective amount of the aforementioned PI3K inhibitor and the aforementioned dual PD-L1/TGF ⁇ inhibitor.
- the method can comprise administering to a subject in need thereof: an effective amount of the aforementioned PI3K inhibitor, such as the aforementioned (S)-2-(1-(9H-purin-6-ylamino)propyl) -3-(3-fluorophenyl)-4H-chromen-4-one; and the aforementioned dual PD-L1/TGF ⁇ inhibitors, such as WBP1126, M7824, SHR-1701, or variants or biosimilars thereof, or a combination thereof.
- the aforementioned PI3K inhibitor such as the aforementioned (S)-2-(1-(9H-purin-6-ylamino)propyl) -3-(3-fluorophenyl)-4H-chromen-4-one
- the aforementioned dual PD-L1/TGF ⁇ inhibitors such as WBP1126, M7824, SHR-1701, or variants or biosimilars thereof, or a combination thereof.
- the PI3K inhibitor can be administered concurrently with the dual PD-L1/TGF ⁇ inhibitor.
- the PI3K inhibitor can be administered after the dual PD-L1/TGF ⁇ inhibitor.
- the PI3K inhibitor can be administered before the dual PD-L1/TGF ⁇ inhibitor.
- it also includes administering to a subject in need thereof an effective amount of the aforementioned small molecule TGF ⁇ inhibitor.
- the tumor can include solid tumors and non-solid tumors.
- the tumor may comprise a tumor with abnormal PI3K expression.
- the tumor may comprise a tumor with abnormal PD-L1 expression.
- the tumor may comprise a tumor with abnormal expression of TGF[beta].
- the tumor may comprise a gastrointestinal tumor, melanoma, or lymphoma.
- the methods of the present application delay resistance compared to the time at which resistance typically develops when treating a subject with either an agent or an inhibitor alone as a monotherapy.
- resistance is delayed by at least 2 weeks, eg, at least 2 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 8 months, 10 months, 12 months, 1 year, 2 years, 4 years, 6 years, 8 years or more.
- remission e.g., complete remission or partial remission
- remission (eg, complete remission or partial remission) extends for at least 2 weeks, eg, at least 2 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 8 months, 10 months, 12 months, 1 year, 2 years, 4 years, 6 years, 8 years or more.
- the addition of a PI3K inhibitor or a second agent to the treatment regimen increases or restores sensitivity to the cancer-resistant agent.
- adding a second agent to a treatment regimen increases or restores sensitivity to a cancer-resistant PI3K inhibitor.
- MRD minimal residual disease
- the methods described herein include selecting a subject for treatment with a combination of a PI3K inhibitor and a second agent.
- a subject eg, a patient suffering from a cancer, eg, a cancer described herein
- selection is based on the presence of MRD above a preselected level (eg, 1 malignant cell in 100 normal cells, 1 malignant cell in 1000 normal cells, or 1 in 10,000 normal cells malignant tumor cells).
- Methods for monitoring minimal residual disease negativity (MRD) are known in the art. See, eg, Zhou, J. et al., Blood, 2007, 110:1607-1611. Such methods include DNA-based tests or RNA-based tests.
- MRD is monitored using flow cytometry, sequencing, or PCR.
- the present application provides the use of the aforementioned pharmaceutical combination or the aforementioned pharmaceutical composition in the preparation of a medicament for treating and/or preventing tumors.
- the use of the aforementioned PI3K inhibitors and the aforementioned inhibitors of immune checkpoints in the preparation of medicaments for treating and/or preventing tumors For example, the use of the aforementioned PI3K inhibitor and the aforementioned TGF ⁇ inhibitor in the preparation of a medicament for treating and/or preventing tumors.
- the present application provides the aforementioned pharmaceutical combination or the aforementioned pharmaceutical composition for treating and/or preventing tumors.
- the present application provides a method of inhibiting tumor growth, the method comprising contacting the tumor with the aforementioned pharmaceutical combination or the aforementioned pharmaceutical composition.
- the method comprises contacting the tumor with the aforementioned PI3K inhibitor and the aforementioned inhibitor of immune checkpoints. In certain embodiments, the method comprises contacting the tumor with the aforementioned PI3K inhibitor and the aforementioned TGF ⁇ inhibitor. In certain embodiments, the method comprises contacting the tumor with the aforementioned PI3K inhibitor, the aforementioned inhibitor of an immune checkpoint, and the aforementioned TGF ⁇ inhibitor.
- the present application provides a method of inhibiting tumor growth, the method comprising contacting the tumor with the aforementioned PI3K inhibitor and the aforementioned dual PD-L1/TGF ⁇ inhibitor.
- the present application provides a kit comprising: (1) a first container, and the aforementioned PI3K inhibitor located in the first container; (2) a second container, and located in the first container The aforementioned dual PD-L1/TGF ⁇ inhibitor in two containers.
- the present application provides a kit, which may include: (1) a first container, and the aforementioned PI3K inhibitor located in the first container; (2) a second container, and located in the first container The aforementioned inhibitor of immune checkpoint or the aforementioned TGF ⁇ inhibitor in the second container.
- the kit further comprises (3) a third container, and the aforementioned inhibitor of immune checkpoint or the aforementioned TGF ⁇ inhibitor located in the third container, the agent in the third container Different from the medicament in the second container.
- the dosage form of the drug in the kit can be an oral dosage form or an injectable dosage form.
- the kit may also contain instructions.
- mice (16-20 g) aged 6-8 weeks were purchased from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd., and 500,000 A20 cells were inoculated subcutaneously in each mouse, which were inoculated on the right back of the mouse.
- the tumor volume grew to about 60mm 3 , the patients were randomly assigned to the control group and the experimental group.
- the percent median regression for a group on a given day is then obtained by taking the median individual percent regression calculated for each animal in the group on that day.
- the date of the calculation was determined on the day the ⁇ T/ ⁇ C (ie, the ratio of the median change from baseline in tumor volume between the experimental and experimental groups) was calculated, unless the median percent regression did not represent activity in that group. In that case, the first day when the median percent regression was maximal was determined to be the day.
- Regression was defined as partial (PR) if the tumor volume dropped to 50% of the tumor volume at the start of treatment. Complete regression (CR) was considered to have been achieved when the tumor volume was below 14 mm3 or could not be recorded.
- Example 1.1 Study on the combination of CN401 (Tenalisib) and CN202 (WBP1126) (5mg/kg) in A20 mouse B-cell lymphoma model (see Table 2 for experimental design)
- 6-8-week-old balb/c mice (18-20 g) were purchased from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd. Each mouse was inoculated with 500,000 A20 cells subcutaneously and inoculated on the right back of the mouse. Treatment was initiated when the tumor had grown to about 62 mm in volume. Among them, CN401 was orally administered at 150 mg/kg twice a day for 3 weeks.
- CN202 was administered by intraperitoneal injection at a dose of 5 mg/kg 3 times a week for 3 weeks.
- the control group received vehicle without active product (0.5% MC and PBS). Tumor size and body weight were measured three times a week.
- This animal experiment was carried out in accordance with the requirements of AAALAC, and was approved by the Bikai Animal Experiment Center IACUC to conduct this animal experiment.
- Blank control group PBS i.p.tiw ⁇ 3weeks+0.5%MC p.o.bid ⁇ 3weeks
- Blank control group PBS i.p.tiw ⁇ 3weeks+0.5%MC p.o.bid ⁇ 3weeks
- CN401 150mg/kg p.o.bid ⁇ 3weeks 3
- CN202 5mg/kg i.p.tiw ⁇ 3weeks 4
- Example 1.2 Study on the combination of CN401 and CN202 (15mg/kg) in A20 mouse B-cell lymphoma model (see Table 4 for experimental design)
- Example 1.1 Refer to the test method of Example 1.1, except that the dosage of CN202 is replaced by 5 mg/kg to 15 mg/kg.
- Blank control group PBS i.p.tiw ⁇ 3weeks+0.5%MC p.o.bid ⁇ 3weeks
- Blank control group PBS i.p.tiw ⁇ 3weeks+0.5%MC p.o.bid ⁇ 3weeks
- CN401 150mg/kg PBS i.p.tiw ⁇ 3weeks+0.5%MC p.o.bid ⁇ 3weeks
- CN202 15mg/kg i.p.tiw ⁇ 3weeks 4
- CN401 combined with different doses of CN202 (5mg/kg, 15mg/kg) produced a synergistic effect on tumor inhibition, and had no significant effect on mouse body weight, showing good tolerance .
- 6-8-week-old balb/c mice (18-20 g) were purchased from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd. Each mouse was inoculated with 500,000 A20 cells subcutaneously and inoculated on the right back of the mouse. Treatment was initiated when the tumor had grown to approximately 80 mm in volume. Among them, CN202 was administered by intraperitoneal injection, 3 times a week, at a dose of 5 mg/kg for 3 weeks. CN401 was administered orally at 150 mg/kg twice daily for 3 weeks. The control group received vehicle without active product (0.5% MC and PBS). Tumor size and body weight were measured three times a week. This animal experiment was carried out in accordance with the requirements of AAALAC, and was approved by the Bikai Animal Experiment Center IACUC to conduct this animal experiment.
- Blank control group PBS i.p.tiw ⁇ 3weeks+0.5%MC p.o.bid ⁇ 3weeks
- Blank control group PBS i.p.tiw ⁇ 3weeks+0.5%MC p.o.bid ⁇ 3weeks
- Blank control group PBS i.p.tiw ⁇ 3weeks+0.5%MC p.o.bid ⁇ 3weeks
- CN202 5mg/kg i.p.tiw ⁇ 3weeks 3
- CN401 150mg/kg p.o.bid ⁇ 3weeks 4
- Example 2.1 The test method of Example 2.1 was followed, except that the PI3K inhibitor was administered orally at 150 mg/kg twice a day from the CN401 (Tenalisib) administration, and was replaced by Alpelisib at 50 mg/kg orally once a day for 3 weeks , for 3 weeks.
- 6-8-week-old balb/c mice (18-20 g) were purchased from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd. Each mouse was inoculated with 500,000 A20 cells subcutaneously and inoculated on the right back of the mouse. Treatment was initiated when the tumor had grown to about 62 mm in volume. CN401 was administered orally at 150 mg/kg twice daily for 3 weeks. Among them, the anti-PD-L1 antibody (Atezolizumab) was administered by intraperitoneal injection twice a week at a dose of 5 mg/kg for 3 weeks. The control group received vehicle without active product (0.5% MC and PBS). Tumor size and body weight were measured three times a week. This animal experiment was carried out in accordance with the requirements of AAALAC, and was approved by the Bikai Animal Experiment Center IACUC to conduct this animal experiment.
- AAALAC AAALAC
- Example 4 Study on the combination of CN202 and nab-pac and the combination of CN401, CN202 and nab-pac in the EMT-6 tumor model (see Table 12 for the experimental design)
- balb/c mice (18-20g) were purchased from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd., and each mouse was inoculated with 500,000 EMT-6 cells (mouse triple negative breast cancer cells) , inoculated into the 2-3 pairs of mammary fat pads from top to bottom on the left side of the thorax of mice. Group dosing treatment was started when the tumor volume grew to about 87 mm 3 .
- CN401 was administered orally at 150 mg/kg twice daily for 4 weeks.
- CN202 and nab-paclitaxel were administered by intraperitoneal injection.
- CN202 was administered 3 times a week at a dose of 15 mg/kg for 2 weeks; the same dose, CN202 was administered once a week for 2 weeks.
- Nab-paclitaxel was administered twice weekly at a dose of 10 mg/kg for 2 weeks.
- the control group received vehicle without active product (0.5% MC and PBS). Tumor size and body weight were measured three times a week. This animal experiment was carried out in accordance with the requirements of AAALAC, and was approved by the Bikai Animal Experiment Center IACUC to conduct this animal experiment.
Abstract
Description
组别 | 数量 | 给药方式 |
1 | 8 | 空白对照组(PBS i.p.tiw×3weeks+0.5%MC p.o.bid×3weeks) |
2 | 8 | CN401 150mg/kg,p.o.bid×3weeks |
3 | 8 | CN202 5mg/kg,i.p.tiw×3weeks |
4 | 8 | CN401 150mg/kg,p.o.bid×3weeks+CN202 5mg/kg,i.p.tiw×3weeks |
组别 | 数量 | 给药方式 |
1 | 8 | 空白对照组(PBS i.p.tiw×3weeks+0.5%MC p.o.bid×3weeks) |
2 | 8 | CN401 150mg/kg,p.o.bid×3weeks |
3 | 8 | CN202 15mg/kg,i.p.tiw×3weeks |
4 | 8 | CN401 150mg/kg,p.o.bid×3weeks+CN202 15mg/kg,i.p.tiw×3weeks |
组别 | 数量 | 给药方式 |
1 | 7 | 空白对照组(PBS i.p.tiw×3weeks+0.5%MC p.o.bid×3weeks) |
2 | 7 | CN202 5mg/kg i.p.tiw×3weeks |
3 | 7 | CN401 150mg/kg p.o.bid×3weeks |
4 | 7 | CN202 5mg/kg i.p.tiw×3weeks+CN401 150mg/kg p.o.bid×3weeks |
组别 | 数量 | 给药计划 |
1 | 7 | 空白对照组(PBS i.p.tiw×3weeks+0.5%MC p.o.bid×3weeks) |
2 | 7 | CN202 5mg/kg i.p.tiw×3weeks |
3 | 7 | Alpelisib 50mg/kg p.o.qd×3weeks |
4 | 7 | CN202 5mg/kg i.p.tiw×3weeks+Alpelisib 50mg/kg p.o.qd×3weeks |
Claims (105)
- 一种药物组合,包含磷酸肌醇3-激酶(PI3K)抑制剂和第二治疗剂,其中所述第二治疗剂为免疫检查点的抑制剂,TGFβ抑制剂,双功能免疫检查点/TGFβ抑制剂或它们的组合。
- 根据权利要求1所述的药物组合,其中所述免疫检查点的抑制剂包括能够阻断程序性死亡1(PD-1)与程序性死亡配体1(PD-L1)相互作用的试剂。
- 根据权利要求1-2中任一项所述的药物组合,其中所述免疫检查点的抑制剂包括程序性死亡配体1(PD-L1)和/或程序性死亡1(PD-1)的抑制剂。
- 根据权利要求1-3中任一项所述的药物组合,其中所述双功能免疫检查点/TGFβ抑制剂包括PD-L1/TGFβ双重抑制剂,或PD-1/TGFβ双重抑制剂。
- 根据权利要求1-4中任一项所述的药物组合,所述药物组合包括:1)PD-L1抑制剂和PI3K抑制剂的组合;2)TGFβ抑制剂和PI3K抑制剂的组合;3)PD-1抑制剂、TGFβ抑制剂和PI3K抑制剂的组合;4)PD-L1抑制剂、TGFβ抑制剂和PI3K抑制剂的组合;5)PD-L1/TGFβ双重抑制剂和PI3K抑制剂的组合;或6)PD-1/TGFβ双重抑制剂和PI3K抑制剂的组合。
- 根据权利要求1-5中任一项所述的药物组合,其中所述免疫检查点的抑制剂包括核酸,抗体或其抗原结合片段,融合蛋白或化合物。
- 根据权利要求6所述的药物组合,其中所述抗体选自:人抗体、人源化抗体、嵌合抗体、多特异性抗体、单克隆抗体和多克隆抗体。
- 根据权利要求6-7中任一项所述的药物组合,其中所述抗原结合片段选自:Fab、Fab’、F(ab’) 2、Fv、scFv、双抗体、Fd、dAb、VHH、大抗体和互补决定区(CDR)片段。
- 根据权利要求6-8中任一项所述的药物组合,其中所述抗体或其抗原结合片段包含含有HCDR1,HCDR2和HCDR3的重链可变区(VH)。
- 根据权利要求6-9中任一项所述的药物组合,其中所述抗体或其抗原结合片段还包含或不包含CH1结构域。
- 根据权利要求10所述的药物组合,其中所述抗体或其抗原结合片段还包含或不包含CH2和CH3结构域。
- 根据权利要求6-9中任一项所述的药物组合,其中所述抗体或其抗原结合片段还包含抗体重链恒定区。
- 根据权利要求12所述的药物组合,其中所述抗体重链恒定区为人抗体重链恒定区。
- 根据权利要求13所述的药物组合,其中所述人抗体重链恒定区选自源自下组的恒定区:IgG1、IgG2、IgG3、IgG4和它们的变体。
- 根据权利要求6-14中任一项所述的药物组合,其中所述抗体或其抗原结合片段还包含含有LCDR1,LCDR2,LCDR3的轻链可变区(VL)。
- 根据权利要求15所述的药物组合,其中所述抗体或其抗原结合片段还包含轻链恒定区(CL)。
- 根据权利要求1-16中任一项所述的药物组合,其中所述免疫检查点的抑制剂包含抗PD-L1抗体或其抗原结合片段,或抗PD-1抗体或其抗原结合片段。
- 根据权利要求17所述的药物组合,其中所述抗PD-L1抗体或其抗原结合片段包含抗体的重链可变区,其中所述重链可变区包含HCDR1,HCDR2,HCDR3,它们各自分别与以下分子的HCDR1,HCDR2,HCDR3具有至少约80%的序列同一性:Atezolizumab、Avelumab、BMS-936559、MPDL3280A(RG7446)或durvalumab(MEDI-4736)。
- 根据权利要求17-18中任一项所述的药物组合,其中所述抗PD-L1抗体或其抗原结合片段包含抗体的重链可变区,其中所述重链可变区分别与以下分子的重链可变区具有至少约80%的序列同一性:Atezolizumab、Avelumab、BMS-936559、MPDL3280A或durvalumab。
- 根据权利要求17-19中任一项所述的药物组合物,其中所述抗PD-L1抗体或其抗原结合片段包含抗体的重链,其中所述重链分别与以下分子的重链具有至少约80%的序列同一性:Atezolizumab、Avelumab、BMS-936559、MPDL3280A或durvalumab。
- 根据权利要求17-20中任一项所述的药物组合,其中所述抗PD-L1抗体或其抗原结合片段还包含抗体的轻链可变区,其中所述轻链可变区包含LCDR1,LCDR2,LCDR3,它们各自分别与以下分子的LCDR1,LCDR2,LCDR3具有至少约80%的序列同一性:Atezolizumab、Avelumab、BMS-936559、MPDL3280A或durvalumab。
- 根据权利要求17-21中任一项所述的药物组合物,其中所述抗PD-L1抗体或其抗原结合片段还包含抗体的轻链可变区,其中所述轻链可变区分别与以下分子的轻链可变区具有至少约80%的序列同一性:Atezolizumab、Avelumab、BMS-936559、MPDL3280A或durvalumab。
- 根据权利要求17-22中任一项所述的药物组合物,其中所述抗PD-L1抗体或其抗原结合片段还包含抗体的轻链,其中所述轻链分别与以下分子的轻链具有至少约80%的序列同一性:Atezolizumab、Avelumab、BMS-936559、MPDL3280A或durvalumab。
- 根据权利要求17-23中任一项所述的药物组合,其中所述抗PD-L1抗体或其抗原结合片 段包括:Atezolizumab、Avelumab、BMS-936559、MPDL3280A或durvalumab,或其抗原结合片段,或其变体或生物类似物,或其组合。
- 根据权利要求17所述的药物组合,其中所述抗PD-L1抗体或其抗原结合片段包含抗体的重链可变区,其中所述重链可变区包括一个或多个选自下组的重链可变区CDRs(HCDRs):(a)具有与SEQ ID NO:1所示氨基酸序列至少约70%序列同一性的HCDR1;(b)具有与SEQ ID NO:2至少约70%序列同一性的HCDR2;和(c)具有与SEQ ID NO:3至少约70%序列同一性的HCDR3。
- 根据权利要求25所述的药物组合,其中所述抗PD-L1抗体或其抗原结合片段包含抗体的重链可变区,其中所述重链可变区包括一个或多个选自下组的HCDRs:(a)具有SEQ ID NO:1所示氨基酸序列的HCDR1或者通过氨基酸加成、消除或者取代反应所得到的具有与SEQ ID NO:1所示氨基酸序列不超过2个氨基酸差异的HCDR1;(b)具有SEQ ID NO:2所示氨基酸序列的HCDR2或者通过氨基酸加成、消除或者取代反应所得到的具有与SEQ ID NO:2所示氨基酸序列不超过2个氨基酸差异的HCDR2;和(c)具有SEQ ID NO:3所示氨基酸序列的HCDR3或者通过氨基酸加成、消除或者取代反应所得到的具有与SEQ ID NO:3所示氨基酸序列不超过2个氨基酸差异的HCDR3。
- 根据权利要求17所述的药物组合,其中所述抗PD-L1抗体或其抗原结合片段包含抗体的重链可变区,其中所述重链可变区包含HCDR1,HCDR2,HCDR3,所述HCDR1包含与SEQ ID NO:1所示氨基酸序列至少约70%序列同一性的氨基酸序列,所述HCDR2包含与SEQ ID NO:2所示氨基酸序列至少约70%序列同一性的氨基酸序列,所述HCDR3包含与SEQ ID NO:3所示氨基酸序列至少约70%序列同一性的氨基酸序列。
- 根据权利要求27所述的药物组合,其中所述抗PD-L1抗体或其抗原结合片段包含抗体的重链可变区,其中所述重链可变区包含HCDR1,HCDR2,HCDR3,所述HCDR1包含SEQ ID NO:1所示的氨基酸序列或通过氨基酸加成、消除或者取代反应所得到的具有与SEQ ID NO:1所示的氨基酸序列不超过2个氨基酸差异的氨基酸序列;所述HCDR2包含SEQ ID NO:2所示的氨基酸序列或通过氨基酸加成、消除或者取代反应所得到的具有与SEQ ID NO:2所示的氨基酸序列不超过2个氨基酸差异的氨基酸序列;所述HCDR3包含SEQ ID NO:3所示的氨基酸序列或通过氨基酸加成、消除或者取代反应所得到的具有与SEQ ID NO:3所示的氨基酸序列不超过2个氨基酸差异的氨基酸序列。
- 根据权利要求28所述的药物组合,其中所述抗PD-L1抗体或其抗原结合片段包含抗体的重链可变区,其中所述重链可变区包含选自下组的氨基酸序列:(a)SEQ ID NO:4所示的 氨基酸序列;(b)与SEQ ID NO:4所示的氨基酸序列至少约85%,90%,95%或者99%序列同一性的氨基酸序列;和(c)通过加成、消除或取代反应所得到的与SEQ ID NO:4所示的氨基酸序列具有1个或更多差异的氨基酸序列。
- 根据权利要求1-29中任一项所述的药物组合,其中所述TGFβ抑制剂结合TGFβ1、TGFβ2或TGFβ3。
- 根据权利要求1-30中任一项所述的药物组合,其中所述TGFβ抑制剂结合TGFβ或转化生长因子β受体(TGFβR)。
- 根据权利要求1-31中任一项所述的药物组合,其中所述TGFβ抑制剂结合TGFβI型受体(TGFβRI),TGFβII型受体(TGFβRII)或TGFβIII型受体(TGFβRIII)。
- 根据权利要求1-32中任一项所述的药物组合,其中所述TGFβ抑制剂包括:1)抗TGFβ抗体或其抗原结合片段;2)抗TGFβR抗体或其抗原结合片段;3)小分子TGFβ抑制剂;4)包含转化生长因子β受体II(TGFβRII)或其功能活性片段、或其变体或生物类似物的蛋白质,或它们的组合。
- 根据权利要求33所述的药物组合,其中所述抗TGFβ抗体或其抗原结合片段包含抗体的重链可变区,其中所述重链可变区包含HCDR1,HCDR2,HCDR3,它们各自分别与Fresolimumab分子的HCDR1,HCDR2,HCDR3具有至少约80%的序列同一性。
- 根据权利要求33-34中任一项所述的药物组合,其中所述抗TGFβ抗体或其抗原结合片段包含抗体的重链可变区,其中所述重链可变区与Fresolimumab分子的重链可变区具有至少约80%的序列同一性。
- 根据权利要求33-35中任一项所述的药物组合,其中所述抗TGFβ抗体或其抗原结合片段包含抗体的重链,其中所述重链与Fresolimumab分子的重链具有至少约80%的序列同一性。
- 根据权利要求33-36中任一项所述的药物组合,其中所述抗TGFβ抗体或其抗原结合片段包含抗体的轻链可变区,其中所述轻链可变区包含LCDR1,LCDR2,LCDR3,它们各自分别与Fresolimumab分子的LCDR1,LCDR2,LCDR3具有至少约80%的序列同一性。
- 根据权利要求33-37中任一项所述的药物组合,其中所述抗TGFβ抗体或其抗原结合片段包含抗体的轻链可变区,其中所述轻链可变区与Fresolimumab分子的轻链可变区具有至少约80%的序列同一性。
- 根据权利要求33-38中任一项所述的药物组合,其中所述抗TGFβ抗体或其抗原结合片段 包含抗体的轻链,其中所述轻链与Fresolimumab分子的轻链具有至少约80%的序列同一性。
- 根据权利要求33-39中任一项所述的药物组合,其中所述抗TGFβ抗体或其抗原结合片段包括:Fresolimumab,或其抗原结合片段,或其变体或生物类似物。
- 根据权利要求33-40中任一项所述的药物组合,其中所述小分子TGFβ抑制剂包括以下化合物:SB525334、SD-208、SB431542、LY2109761、LY2157299、GW788388、RepSox、SIS3、LDN-193189、EW-7197、LY364947、或其组合。
- 根据权利要求33-41中任一项所述的药物组合,其中所述TGFβRII包括具有野生型人TGFβ受体2型同种型A序列的多肽,或具有野生型人TGFβ受体2型同种型B序列的多肽,或与其氨基酸序列具有基本相同的序列的多肽。
- 根据权利要求33-42中任一项所述的药物组合,其中所述TGFβRII或其功能活性片段包括人TGFβRII胞外域(ECD)或者与其氨基酸序列基本相同的序列。
- 根据权利要求43所述的药物组合,其中所述TGFβRII或其功能活性片段包含:(a)SEQ ID NO:6所示的氨基酸序列;(b)具有与SEQ ID NO:6所示的氨基酸序列至少约85%序列同一性的氨基酸序列;或(c)具有与SEQ ID NO:6所示的氨基酸序列相比,添加,缺失和/或取代一个或多个氨基酸的氨基酸序列。
- 根据权利要求1-44中任一项所述的药物组合,其中所述双功能免疫检查点/TGFβ抑制剂为融合蛋白。
- 根据权利要求4-45中任一项所述的药物组合,其中所述PD-L1/TGFβ双重抑制剂或PD-1/TGFβ双重抑制剂为融合蛋白。
- 根据权利要求4-46中任一项所述的药物组合,其中所述PD-L1//TGFβ双重抑制剂包含PD-L1靶向部分和TGFβ受体结构域,所述TGFβ受体结构域包含转化生长因子β受体II(TGFβRII)或其功能活性片段。
- 根据权利要求4-47中任一项所述的药物组合,其中所述PD-L1//TGFβ双重抑制剂包含多肽,其中所述多肽至少包含:(i)抗PD-L1抗体的重链可变区;和(ii)TGFβRII或其功能活性片段。
- 根据权利要求48所述的药物组合,其中所述抗PD-L1抗体重链可变区包含HCDR1,HCDR2,HCDR3;其中所述HCDR1包含与SEQ ID NO:1所示氨基酸序列至少约70%序列同一性的氨基酸序列,所述HCDR2包含与SEQ ID NO:2所示氨基酸序列至少约70% 序列同一性的氨基酸序列,且所述HCDR3包含与SEQ ID NO:3所示氨基酸序列至少约70%序列同一性的氨基酸序列;或其中所述HCDR1,HCDR2,HCDR3分别与以下分子的HCDR1,HCDR2,HCDR3具有至少约80%的序列同一性:Atezolizumab、Avelumab、BMS-936559、MPDL3280A(RG7446)或durvalumab(MEDI-4736)。
- 根据权利要求49所述的药物组合,其中所述抗PD-L1抗体重链可变区包含HCDR1,HCDR2,HCDR3,所述HCDR1包含SEQ ID NO:1所示的氨基酸序列或通过氨基酸加成、消除或者取代反应所得到的具有与SEQ ID NO:1所示的氨基酸序列不超过2个氨基酸差异的氨基酸序列;所述HCDR2包含SEQ ID NO:2所示的氨基酸序列或通过氨基酸加成、消除或者取代反应所得到的具有与SEQ ID NO:2所示的氨基酸序列不超过2个氨基酸差异的氨基酸序列;所述HCDR3包含SEQ ID NO:3所示的氨基酸序列或通过氨基酸加成、消除或者取代反应所得到的具有与SEQ ID NO:3所示的氨基酸序列不超过2个氨基酸差异的氨基酸序列。
- 根据权利要求50所述的药物组合,其中所述抗PD-L1抗体重链可变区包含选自下组的氨基酸序列:(a)SEQ ID NO:4所示的氨基酸序列;(b)与SEQ ID NO:4所示的氨基酸序列至少约85%,90%,95%或者99%序列同一性的氨基酸序列;(c)通过加成、消除或取代反应所得到的与SEQ ID NO:4所示的氨基酸序列具有1个或更多差异的氨基酸序列;和(d)与以下分子的重链可变区具有至少约80%的序列同一性的氨基酸序列:Atezolizumab、Avelumab、BMS-936559、MPDL3280A或durvalumab。
- 根据权利要求47所述的药物组合,其中所述TGFβRII或其功能活性片段包含:(a)SEQ ID NO:6所示的氨基酸序列;(b)具有与SEQ ID NO:6所示的氨基酸序列至少约85%序列同一性的氨基酸序列;或(c)具有与SEQ ID NO:6所示的氨基酸序列相比,添加,缺失和/或取代一个或多个氨基酸的氨基酸序列。
- 根据权利要求47所述的药物组合,其中所述多肽还包含连接子,所述连接子将所述抗PD-L1的抗体或其抗原结合片段的重链可变区的C末端与所述TGFβRII或其功能活性片段的N末端相连接。
- 根据权利要求47所述的药物组合,所述多肽还包括CH2、CH3结构域,所述多肽自N末端至C末端依次包含抗PD-L1抗体的重链可变区(VH)、CH2、CH3结构域和TGFβRII或其功能活性片段,所述CH3结构域的C末端与所述TGFβRII或其功能活性片段N末端通 过连接子相连接。
- 根据权利要求54所述的药物组合,其中所述CH2、CH3结构域源自IgG。
- 根据权利要求53-55中任一项所述的药物组合,其中所述连接子为肽连接子。
- 根据权利要求56所述的药物组合,其中所述肽连接子的氨基酸序列为(G 4S) x,其中x为3-6中的任意整数。
- 根据权利要求57所述的药物组合,其中所述肽连接子包含选自下组氨基酸序列:(a)SEQ ID NO:5所示的氨基酸序列;(b)具有与SEQ ID NO:5所示的氨基酸序列至少约85%,90%,95%或者99%序列同一性的氨基酸序列;和(c)通过加成、消除或取代反应所得到的与SEQ ID NO:5所示的氨基酸序列具有1个或更多差异的氨基酸序列。
- 根据权利要求48-58所述的药物组合,其中所述多肽包含选自下组的氨基酸序列:(a)SEQ ID NO:7所示的氨基酸序列;(b)具有与SEQ ID NO:7所示的氨基酸序列至少约85%,90%,95%或者99%序列同一性的氨基酸序列;(c)通过加成、消除或取代反应所得到的与SEQ ID NO:7所示的氨基酸序列具有1个或更多差异的氨基酸序列。
- 根据权利要求1-59中任一项所述的药物组合,其中所述PD-L1//TGFβ双重抑制剂包含两条权利要求48-59中任一项所述多肽。
- 根据权利要求1-60中任一项所述的药物组合,其中所述PI3K抑制剂为PI3Kδ/γ双重抑制剂。
- 根据权利要求1-61中任一项所述的药物组合,其中所述PI3K抑制剂包括式(IA-I)、(IA-II)、(IA-III)、或(IA-IV)所示的化合物:或它们的对映异构体、对映异构体的混合物、两种或更多种非对映异构体的混合物、同位素变体、药学上可接受的盐、溶剂化物、水合物或前药,其中每次出现的R独立地选自氢、卤素、-OR a、CN、经取代或未经取代的C 1-6烷基、经取代或未经取代的C 2-6烯基、经取代或未经取代的C 2-6炔基、经取代或未经取代的C 3-8环烷基和经取代或未经取代的杂环基团;R 1和R 2可相同或不同并且独立地选自氢、卤素和经取代或未经取代的C 1-6烷基,或与共有原子直接结合的R 1和R 2可连接形成=O基或经取代或未经取代的饱和或不饱和3-10元环,包括与R 1和R 2结合的碳原子,所述环可任选地包括一个或多个相同或不同且选自O、NR a和S的杂原子;Cy 1为选自经取代或未经取代的C 3-8环烷基、经取代或未经取代的具有至少一个选自N、O和S的杂原子的3至15元杂环基团、经取代或未经取代的C 6-20芳基和经取代或未经取代的具有一个或多个选自N、O和S的杂原子的5至14元杂芳基的单环基团;每次出现的R a可相同或不同且独立地选自氢、卤素、羟基、氰基、经取代或未经取代的C 1-6烷基;-NR cR d,其中R c,R d独立地选自氢、卤素、羟基、氰基、经取代或未经取代的C 1-6烷基和C 1-6烷氧基,和-OR c,其中R c为经取代或未经取代的C 1-6烷基;n为1-4的整数;并且q为0、1或2;每次出现的X独立地选自CR 3或N;并且每次出现的R 3独立地选自氢、羟基、卤素、羧基、氰基、硝基、经取代或未经取代的C 1-8烷基、经取代或未经取代的C 1-8烷氧基、经取代或未经取代的C 2-10烯基、经取代或未经取代的C 2-12炔基、经取代或未经取代的C 6-20芳基、经取代或未经取代的C 6- 20芳基C 1-8烷基、经取代或未经取代的C 3-20环烷基、经取代或未经取代的C 3-20环烷基C 1-8烷基、经取代或未经取代的C 3-8环烯基C 1-8烷基、经取代或未经取代的C 3-8环烯基、经取代或未经取代的具有一个或多个选自N、O和S的杂原子的5至14元杂芳基、经取代或未经取代的具有一个或多个选自N、O和S的杂原子的5至14元杂芳基C 1-8烷基、经取代或未经取代的具有至少一个选自N、O和S的杂原子的3至15元杂环、经取代或未经取代的具有至少一个选自N、O和S的杂原子的3至15元杂环基C 1-8烷基环、经取代或未经取代的胍、-C00R x、-C(O)R x、-C(S)R x、-C(O)NR xR y、-C(O)ONR xR y,-NR yR z、-NR xCONR yR z,-N(R x)SOR y、-N(Rx)SO 2R y、-(=N-N(R x)R y)、-NR xC(O)OR y、-NR xR y、-NR xC(O)R y-、-NR xC(S)R y、-NR xC(S)NR yR z、-SONR xR y-、-SO 2NR xR y-、-OR x、-OR xC(O)NR yR z、-OR xC(O)OR y-、-OC(O)R x、-OC(O)NR xR y、-R xNR yC(O)R z、-R xOR y、-R xC(O)OR y、-R xC(O)NR yR z、-R xC(O)R x、-R xOC(O)R x、-SR x、-SOR x、-SO 2R x和-ONO 2,其中以上每个基团中的R x、R y和R z可为氢、经取代或未经取代的C 1-8烷基、经取代或未经取代的C 1-8烷氧基、经取代或未经取代的C 2-10烯基、经取代或未经取代的C 2-12炔基、经取代或未经取代的C 6-20芳基、经取代或未经取代的C 6-20芳基C 1-8烷基、经 取代或未经取代的C 3-20环烷基、经取代或未经取代的C 3-20环烷基C 1-8烷基、经取代或未经取代的C 3-8环烯基、经取代或未经取代的具有一个或多个选自N、O和S的杂原子的5至14元杂芳基、经取代或未经取代的具有一个或多个选自N、O和S的杂原子的5至14元杂芳基C 1-8烷基、经取代或未经取代的具有至少一个选自N、O和S的杂原子的3至15元杂环、经取代或未经取代的具有至少一个选自N、O和S的杂原子的3至15元杂环基C 1-8烷基环或经取代或未经取代的氨基,或R x、R y和R z的任两个可连接形成经取代或未经取代的饱和或不饱和3-10元环,所述环可任选地包括可能相同或不同且选自O、NR x或S的杂原子,其中R x为氢或经取代或未经取代的烷基。
- 根据权利要求1-62中任一项所述的药物组合,其中所述PI3K抑制剂包括式(IA-V)所示的化合物:或其对映异构体、对映异构体的混合物、两种或更多种非对映异构体的混合物、或同位素变体;或其药学上可接受的盐、溶剂化物、水合物或前药,其中每次出现的R独立地选自氢、卤素、-OR a、CN、经取代或未经取代的C 1-6烷基、经取代或未经取代的C 2-6烯基、经取代或未经取代的C 2-6炔基、经取代或未经取代的C 3-8环烷基和经取代或未经取代的杂环基团;R 1和R 2可相同或不同并且独立地选自氢、卤素和经取代或未经取代的C 1-6烷基,或与共有原子直接结合的R 1和R 2可连接形成=O基或经取代或未经取代的饱和或不饱和3-10元环,包括与R 1和R 2结合的碳原子,所述环可任选地包括一个或多个相同或不同且选自O、NR a和S的杂原子;每次出现的X独立地选自CR 3或N;并且每次出现的R 3独立地选自氢、羟基、卤素、羧基、氰基、硝基、经取代或未经取代的C 1-8烷基、经取代或未经取代的C 1-8烷氧基、经取代或未经取代的C 2-10烯基、经取代或未经取代的C 2-12炔基、经取代或未经取代的C 6-20芳基、经取代或未经取代的C 6-20芳基C 1-8烷基、经取代或未经取代的C 3-20环烷基、经取代或未经取代的C 3-20环烷基C 1-8烷 基、经取代或未经取代的C 3-8环烯基C 1-8烷基、经取代或未经取代的C 3-8环烯基、经取代或未经取代的具有一个或多个选自N、O和S的杂原子的5至14元杂芳基、经取代或未经取代的具有一个或多个选自N、O和S的杂原子的5至14元杂芳基C 1-8烷基、经取代或未经取代的具有至少一个选自N、O和S的杂原子的3至15元杂环、经取代或未经取代的具有至少一个选自N、O和S的杂原子的3至15元杂环基C 1-8烷基环、经取代或未经取代的胍、-C00R x、-C(O)R x、-C(S)R x、-C(O)NR xR y、-C(O)ONR xR y,-NR yR z、-NR xCONR yR z,-N(R x)SOR y、-N(Rx)SO 2R y、-(=N-N(R x)R y)、-NR xC(O)OR y、-NR xR y、-NR xC(O)R y-、-NR xC(S)R y、-NR xC(S)NR yR z、-SONR xR y-、-SO 2NR xR y-、-OR x、-OR xC(O)NR yR z、-OR xC(O)OR y-、-OC(O)R x、-OC(O)NR xR y、-R xNR yC(O)R z、-R xOR y、-R xC(O)OR y、-R xC(O)NR yR z、-R xC(O)R x、-R xOC(O)R x、-SR x、-SOR x、-SO 2R x和-ONO 2,其中以上每个基团中的R x、R y和R z可为氢、经取代或未经取代的C 1-8烷基、经取代或未经取代的C 1-8烷氧基、经取代或未经取代的C 2-10烯基、经取代或未经取代的C 2-12炔基、经取代或未经取代的C 6-20芳基、经取代或未经取代的C 6-20芳基C 1-8烷基、经取代或未经取代的C 3-20环烷基、经取代或未经取代的C 3-20环烷基C 1-8烷基、经取代或未经取代的C 3-8环烯基、经取代或未经取代的具有一个或多个选自N、O和S的杂原子的5至14元杂芳基、经取代或未经取代的具有一个或多个选自N、O和S的杂原子的5至14元杂芳基C 1-8烷基、经取代或未经取代的具有至少一个选自N、O和S的杂原子的3至15元杂环、经取代或未经取代的具有至少一个选自N、O和S的杂原子的3至15元杂环基C 1-8烷基环或经取代或未经取代的氨基,或R x、R y和R z的任两个可连接形成经取代或未经取代的饱和或不饱和3-10元环,所述环可任选地包括可能相同或不同且选自O、NR x或S的杂原子,其中R x为氢或经取代或未经取代的烷基;每次出现的R 5为氢、C 1-6烷基或卤素;n为0、1、2、3或4;并且P为0、1、2、3、4或5。
- 根据权利要求1-63中任一项所述的药物组合,其中所述PI3K抑制剂包括式(IA-VI)所示的化合物:或其对映异构体、对映异构体的混合物、两种或更多种非对映异构体的混合物、或同位素变体;或其药学上可接受的盐、溶剂化物、水合物或前药,其中每次出现的R独立地选自氢、卤素、-OR a、CN、经取代或未经取代的C 1-6烷基、经取代或未经取代的C 2-6烯基、经取代或未经取代的C 2-6炔基、经取代或未经取代的C 3-8环烷基和经取代或未经取代的杂环基团;R 1和R 2可相同或不同并且独立地选自氢、卤素和经取代或未经取代的C 1-6烷基,或与共有原子直接结合的R 1和R 2可连接形成=O基或经取代或未经取代的饱和或不饱和3-10元环,包括与R 1和R 2结合的碳原子,所述环可任选地包括一个或多个相同或不同且选自O、NR a和S的杂原子;每次出现的X独立地选自CR 3或N;并且每次出现的R 3独立地选自氢、羟基、卤素、羧基、氰基、硝基、经取代或未经取代的C 1-8烷基、经取代或未经取代的C 1-8烷氧基、经取代或未经取代的C 2-10烯基、经取代或未经取代的C 2-12炔基、经取代或未经取代的C 6-20芳基、经取代或未经取代的C 6-20芳基C 1-8烷基、经取代或未经取代的C 3-20环烷基、经取代或未经取代的C 3-20环烷基C 1-8烷基、经取代或未经取代的C 3-8环烯基C 1-8烷基、经取代或未经取代的C 3-8环烯基、经取代或未经取代的具有一个或多个选自N、O和S的杂原子的5至14元杂芳基、经取代或未经取代的具有一个或多个选自N、O和S的杂原子的5至14元杂芳基C 1-8烷基、经取代或未经取代的具有至少一个选自N、O和S的杂原子的3至15元杂环、经取代或未经取代的具有至少一个选自N、O和S的杂原子的3至15元杂环基C 1-8烷基环、经取代或未经取代的胍、-C00R x、-C(O)R x、-C(S)R x、-C(O)NR xR y、-C(O)ONR xR y,-NR yR z、-NR xCONR yR z,-N(R x)SOR y、-N(Rx)SO 2R y、-(=N-N(R x)R y)、-NR xC(O)OR y、-NR xR y、-NR xC(O)R y-、-NR xC(S)R y、-NR xC(S)NR yR z、-SONR xR y-、-SO 2NR xR y-、-OR x、-OR xC(O)NR yR z、-OR xC(O)OR y-、-OC(O)R x、-OC(O)NR xR y、-R xNR yC(O)R z、-R xOR y、-R xC(O)OR y、-R xC(O)NR yR z、-R xC(O)R x、-R xOC(O)R x、-SR x、-SOR x、-SO 2R x和- ONO 2,其中以上每个基团中的R x、R y和R z可为氢、经取代或未经取代的C 1-8烷基、经取代或未经取代的C 1-8烷氧基、经取代或未经取代的C 2-10烯基、经取代或未经取代的C 2-12炔基、经取代或未经取代的C 6-20芳基、经取代或未经取代的C 6-20芳基C 1-8烷基、经取代或未经取代的C 3-20环烷基、经取代或未经取代的C 3-20环烷基C 1-8烷基、经取代或未经取代的C 3-8环烯基、经取代或未经取代的具有一个或多个选自N、O和S的杂原子的5至14元杂芳基、经取代或未经取代的具有一个或多个选自N、O和S的杂原子的5至14元杂芳基C 1-8烷基、经取代或未经取代的具有至少一个选自N、O和S的杂原子的3至15元杂环、经取代或未经取代的具有至少一个选自N、O和S的杂原子的3至15元杂环基C 1-8烷基环或经取代或未经取代的氨基,或R x、R y和R z的任两个可连接形成经取代或未经取代的饱和或不饱和3-10元环,所述环可任选地包括可能相同或不同且选自O、NR x或S的杂原子,其中R x为氢或经取代或未经取代的烷基;每次出现的R 5为氢、C 1-6烷基或卤素;n为0、1、2、3或4;并且P为0、1、2、3、4或5。
- 根据权利要求1-64中任一项所述的药物组合,其中R为氢、卤素、经取代或未经取代的C 1-6烷基或OR a。
- 根据权利要求65所述的药物组合,其中所述R a为烷基。
- 根据权利要求62-67中任一项所述的药物组合,其中所述R 1和R 2各自独立地表示氢或经取代或未经取代的C 1-6烷基。
- 根据权利要求62-68中任一项所述的药物组合,其中所述R 3为碘代、氰基、经取代或未经取代的烷基、经取代或未经取代的炔基、经取代或未经取代的芳基、经取代或未经取代的杂芳基。
- 根据权利要求62-69中任一项所述的药物组合,其中X为CR 3并且每次出现的R 3独立为氢、卤素、羟基或NH 2。
- 根据权利要求62-70中任一项所述的化合物,其中所述R 3为氢。
- 根据权利要求1-71中任一项所述的药物组合,其中所述PI3K抑制剂包括:2-[(6-氨基-9H-嘌呤-9-基)甲基]-6-溴-3-苯基-4H-色烯-4-酮;2-[(6-氨基-9H-嘌呤-9-基)甲基]-3-苯基-4H-色烯-4-酮;2-((9H-嘌呤-6-基硫代)甲基)-3-苯基-4H-色烯-4-酮;2-[(9H-嘌呤-6-基硫代)甲基]-6-溴-3-苯基-4H-色烯-4-酮;2-((4-氨基-1H-吡唑并[3,4-d]嘧啶-1-基)甲基)-6-溴-3-苯基-4!1-色烯-4-酮;2-[(6-氨基-9H-嘌呤-9-基)甲基]-6-溴-3-(4-氟苯基)-4H-色烯-4-酮;2-[(6-氨基-9H-嘌呤-9-基)甲基]-3-(4-氟苯基)-4H-色烯-4-酮;2-[(6-氨基-9H-嘌呤-9-基)甲基]-6-溴-3-邻甲苯基-4H-色烯-4-酮;2-(1-(6-氨基-9H-嘌呤-9-基)乙基)-6-溴-3-苯基-4H-色烯-4-酮;2-(1-(9H-嘌呤-6-基硫代)乙基)-6-溴-3-苯基-4H-色烯-4-酮;2-(1-(6-氨基-9H-嘌呤-9-基)乙基)-3-苯基-4H-色烯-4-酮;(S)-2-(1-(9H-嘌呤-6-基氨基)乙基)-6-溴-3-苯基-4H-色烯-4-酮;2-((9H-嘌呤-6-基氨基)甲基)-6-溴-3-苯基-4H-色烯-4-酮;2-(1-(4-氨基-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-6-溴-3-苯基-4H-色烯-4-酮;2-((6-氨基-9H-嘌呤-9-基)甲基)-6-甲氧基-3-苯基-4H-色烯-4-酮;2-(1-(6-氨基-9H-嘌呤-9-基)乙基)-6-溴-3-(2-氟苯基)-4H-色烯-4-酮;2-((6-氨基-9H-嘌呤-9-基)甲基)-6-溴-3-(2-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-苯基-4H-色烯-4-酮;2-(1-(6-氨基-9H-嘌呤-9-基)丙基)-3-苯基-4H-色烯-4-酮;2-(1-(6-氨基-9H-嘌呤-9-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-((6-氨基-9H-嘌呤-9-基)甲基)-3-(2-氟苯基)-4H-色烯-4-酮;2-(1-(6-氨基-9H-嘌呤-9-基)乙基)-3-(2-氟苯基)-4H-色烯-4-酮;2-(1-(6-氨基-9H-嘌呤-9-基)丙基)-3-(2-氟苯基)-4H-色烯-4-酮;2-(1-(6-氨基-9H-嘌呤-9-基)丙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(6-氨基-9H-嘌呤-9-基)丙基)-3-(4-氟苯基)-4H-色烯-4-酮;2-(1-(6-氨基-9H-嘌呤-9-基)丙基)-6-氟-3-苯基-4H-色烯-4-酮;2-(1-(6-氨基-9H-嘌呤-9-基)乙基)-3-(4-氟苯基)-4H-色烯-4-酮;2-(1-(6-氨基-9H-嘌呤-9-基)乙基)-6-氟-3-苯基-4H-色烯-4-酮;2-(1-(4-氨基-3-(3-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-苯基-4H-色烯-4-酮;2-(1-(4-氨基-3-(3-羟基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-苯基-4H-色烯-4-酮;2-((9H-嘌呤-6-基氨基)甲基)-3-苯基-4H-色烯-4-酮;2-(1-(6-氨基-9H-嘌呤-9-基)乙基)-3-邻甲苯基-4H-色烯-4-酮;2-((9H-嘌呤-6-基氨基)甲基)-3-(2-氟苯基)-4H-色烯-4-酮;2-((9H-嘌呤-6-基氨基)甲基)-3-(3-氟苯基)-4H-色烯-4-酮;(S)-2-(1-(9H-嘌呤-6-基氨基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(6-氨基-9H-嘌呤-9-基)乙基)-6-氟-3-(2-氟苯基)-4H-色烯-4-酮;2-(1-(6-氨基-9H-嘌呤-9-基)乙基)-3-(3,5-二氟苯基)-4H-色烯-4-酮;2-(1-(6-氨基-9H-嘌呤-9-基)乙基)-6-氟-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(3-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(3-羟基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-((4-氨基-3-(3-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)甲基)-3-苯基-4H-色烯-4-酮;2-((4-氨基-3-(3-羟基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)甲基)-3-苯基-4H-色烯-4-酮;2-((4-氨基-3-(3-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)甲基)-3-(3-氟苯基)-4H-色烯-4-酮;2-((4-氨基-3-(3-羟基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)甲基)-3-(3-氟苯基)-4H-色烯-4-酮;(R)-2-(1-(9H-嘌呤-6-基氨基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;(S)-2-(1-(9H-嘌呤-6-基氨基)乙基)-6-氟-3-苯基-4H-色烯-4-酮;2-((4-氨基-3-碘-1H-吡唑并[3,4-d]嘧啶-1-基)甲基)-3-苯基-4H-色烯-4-酮;2-(1-(4-氨基-3-碘-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-苯基-4H-色烯-4-酮;2-(1-(4-氨基-3-碘-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-((4-氨基-3-碘-1H-吡唑并[3,4-d]嘧啶-1-基)甲基)-6-氟-3-苯基-4H-色烯-4-酮;2-(1-(4-氨基-3-碘-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-6-氟-3-苯基-4H-色烯-4-酮;2-(1-(4-氨基-3-碘-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-6-氟-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-碘-1H-吡唑并[3,4-d]嘧啶-1-基)丙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-((4-氨基-3-(吡啶-3-基)-1H-吡唑并[3,4-d]嘧啶-1-基)甲基)-3-苯基-4H-色烯-4-酮;2-((4-氨基-3-(3-羟基丙-1-炔基)-1H-吡唑并[3,4-d]嘧啶-1-基)甲基)-3-苯基-4H-色烯-4-酮;2-((4-氨基-3-(1H-吡唑-4-基)-1H-吡唑并[3,4-d]嘧啶-1-基)甲基)-3-苯基-4H-色烯-4-酮;2-((4-氨基-3-(3-(羟基甲基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)甲基)-3-苯基-4H-色烯-4-酮;2-((4-氨基-3-(1H-吲唑-4-基)-1H-吡唑并[3,4-d]嘧啶-1-基)甲基)-3-苯基-4H-色烯-4-酮;2-((4-氨基-3-(3-氟苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)甲基)-3-苯基-4H-色烯-4-酮;2-((4-氨基-3-(3-羟基丙基)-1H-吡唑并[3,4-d]嘧啶-1-基)甲基)-3-苯基-4H-色烯-4-酮;N-(3-(4-氨基-1-((4-氧代-3-苯基-4H-色烯-2-基)甲基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯基)乙酰胺;2-((4-氨基-3-(3-氟-5-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)甲基)-3-苯基-4H-色烯-4-酮;2-((4-氨基-3-(3-氟-5-羟基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)甲基)-3-苯基-4H-色烯-4-酮;2-((4-氨基-3-(3-氟-5-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)甲基)-3-(3-氟苯基)-4H-色烯-4-酮;2-((4-氨基-3-(3-氟-5-羟基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)甲基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(1H-吡唑-4-基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-苯基-4H-色烯-4-酮;2-(1-(4-氨基-3-(1H-吲唑-6-基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-苯基-4H-色烯-4-酮;2-(1-(4-氨基-3-(3-羟基-3-甲基丁-1-炔基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-苯基-4H-色烯-4-酮;2-(1_(4-氨基-3-(1H-吡唑-4-基)-1H-吡唑并[3,4-(1]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;(S)-2-(1-(9H-嘌呤-6-基氨基)乙基)-3-苯基-4H-色烯-4-酮;(S)-2-(1-(9H-嘌呤-6-基氨基)乙基)-6-氟-3-(3-氟苯基)-4H-色烯-4-酮;2-((4-氨基-3-(1H-吲唑-6-基)-1H-吡唑并[3,4-d]嘧啶-1-基)甲基)-3-苯基-4H-色烯-4-酮;2-(1-(4-氨基-3-(3-氟-5-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(3-氟-5-羟基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(1H-吲唑-4-基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(3,5-二甲基-1H-吡唑-4-基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(3-甲基-1H-吲唑-6-基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(1H-吲唑-6-基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(2-(羟基甲基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(4-氟-3-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(4-氟-3-羟基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(3-羟基丙-1-炔基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(3-氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(3-氟-4-羟基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(3-氯-5-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(3-氯-5-羟基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(3-(三氟甲氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(4-羟基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-((6-氨基-9H-嘌呤-9-基)甲基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(4-氟-2-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(4-氟-2-羟基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-((4-氨基-3-(3-氨基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)甲基)-3-苯基-4H-色烯-4-酮;2-((4-氨基-3-(3-甲基-1H-吲唑-6-基)-1H-吡唑并[3,4-d]嘧啶-1-基)甲基)-3-苯基-4H-色烯-4-酮;2-(1-(4-氨基-3-(2-氨基嘧啶-5-基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(1H-吲哚-6-基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(4-氯-3-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(4-氯-3-羟基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(2-氯-5-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(2-氯-5-羟基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(3,4-二甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(3,4-二羟基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-((4-氨基-3-(3-甲基-1H-吲唑-6-基)-1H-吡唑并[3,4-d]嘧啶-1-基)甲基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(1H-吲哚-5-基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(3-甲基-1H-吲哚-5-基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;叔丁基-(5-(4-氨基-1-(1-(3-(3-氟苯基)-4-氧代-4H-色烯-2-基)乙基)-1H-吡唑并[3,4-d]嘧啶-3-基)噻吩-2-基)氨基甲酸甲酯;2-(1-(4-氨基-3-(5-(氨基甲基)噻吩-2-基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-((4-氨基-3-(3-甲基-1H-吲唑-6-基)-1H-吡唑并[3,4-d]嘧啶-1-基)甲基)-6-氟-3-苯基-4H-色烯-4-酮;2-(1-(4-氨基-3-(3-甲基-1H-吲唑-6-基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-苯基-4H-色烯-4-酮;2-(1-(4-氨基-3-(3-甲基-1H-吲唑-6-基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-6-氟-3-苯基-4H-色烯-4-酮;2-(1-(4-氨基-3-(3-甲基-1H-吲唑-5-基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;N-(4-(4-氨基-1-(1-(3-(3-氟苯基)-4-氧代-4H-色烯-2-基)乙基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯基)乙酰胺;2-(1-(4-氨基-3-(4-氨基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(3-甲基-1H-吲唑-6-基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-6-氟-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(2,3-二氢苯并呋喃-5-基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(3-乙基-1H-吲唑-6-基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(3-甲基-1H-吲哚-6-基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(2-甲氧基嘧啶-5-基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;4-(4-氨基-1-(1-(3-(3-氟苯基)-4-氧代-4H-色烯-2-基)乙基)-1H-吡唑并[3,4-d]嘧啶-3-基)噻吩-2-甲醛;2-(1-(4-氨基-3-(5-(羟基甲基)噻吩-3-基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(2-甲基-1H-苯并[d]咪唑-5-基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(3-甲基-1H-吲唑-6-基)-1H-吡唑并[3,4-d]嘧啶-1-基)丙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(3-甲基-1H-吲哚-6-基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-((6-氨基-9H-嘌呤-9-基)甲基)-6-氟-3-苯基-4H-色烯-4-酮;2-((6-氨基-9H-嘌呤-9-基)甲基)-6-氟-3-(3-氟苯基)-4H-色烯-4-酮;2-((4-氨基-3-(3-氟-5-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)甲基)-6-氟-3-(3-氟苯基)-4H-色烯-4-酮;2-((4-氨基-3-(3-氟-5-羟基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)甲基)-6-氟-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(3-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-6-氟-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(3-羟基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-6-氟-3-(3-氟苯基)-4H-色烯-4-酮;2-((9H-嘌呤-6-基氨基)甲基)-6-氟-3-(3-氟苯基)-4H-色烯-4-酮;2-((9H-嘌呤-6-基氨基)甲基)-6-氟-3-苯基-4H-色烯-4-酮;(R)-2-(1-(9H-嘌呤-6-基氨基)乙基)-6-氟-3-(3-氟苯基)-4H-色烯-4-酮;2-((4-氨基-3-(1H-吡唑-4-基)-1H-吡唑并[3,4-d]嘧啶-1-基)甲基)-6-氟-3-苯基-4H-色烯-4-酮;2-(1-(4-氨基-3-(3,5-二氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(3,5-二氟-4-羟基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-((4-氨基-3-(3,5-二氟-4-甲氧基苯基)-1H-吡唑并[3,4-(1]嘧啶-1-基)甲基)-6-氟-3-(3-氟苯基)-4H-色烯-4-酮;2-((4-氨基-3-(3,5-二氟-4-羟基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)甲基)-6-氟-3-(3-氟苯基)-4H-色烯-4-酮;(+)-2-(1-(4-氨基-3-(3-甲基-1H-吲唑-6-基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;(-)-2-(1-(4-氨基-3-(3-甲基-1H-吲唑-6-基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(3,5-二甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(4-甲氧基-3,5-二甲基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯 基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(2-氟-5-异丙氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(2,3-二氢苯并[b][1,4]二噁英-6-基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(1-苄基-1H-吡唑-4-基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(2-甲基吡啶-4-基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(3,4-二氢-2H-苯并[b][1,4]二氧杂卓-7-基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(6-吗啉基吡啶-3-基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(二苯并[b,d]呋喃-4-基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(4-(苄氧基)-3-氯苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(3-氯-4-异丙氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(3-(二甲基氨基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(4-乙氧基-3-氟苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(4-异丙氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(4-(三氟甲氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(3-(4-乙酰基苯基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4- 酮;2-(1-(4-氨基-3-(4-(苄氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(4-(二甲基氨基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(4-(甲磺酰基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(3-乙氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(苯并[b]噻吩-2-基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(5-氯噻吩-2-基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(3,5-二甲基异噁唑-4-基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(3-丙氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2~(1-(4-氨基-3-(呋喃-2-基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(4-乙氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(3-氯-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(3-氟-4-异丙氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(6-氟吡啶-3-基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(嘧啶-5-基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(3-(甲氧基甲基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(6-羟基萘-2-基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(3-异丙氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(1-甲基-1H-吡唑-4-基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(1,3-二甲基-1H-吲唑-6-基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(2,3-二甲基-2H-吲唑-6-基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(6-甲氧基萘-2-基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(苯并[b]噻吩-3-基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(2,4-二甲氧基嘧啶-5-基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(6-乙氧基萘-2-基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;3-(4-氨基-1-(1-(3-(3-氟苯基)-4-氧代-4H-色烯-2-基)乙基)-1H-吡唑并[3,4-d]嘧啶-3-基)-N-环丙基苯甲酰胺;2-(1-(4-氨基-3-(3-(吗啉-4-羰基)苯基)-1H-吡唑并[3,4-(1]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;2-(1-(4-氨基-3-(3-(二氟甲氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮;5-(4-氨基-1-(1-(3-(3-氟苯基)-4-氧代-4H-色烯-2-基)乙基)-1H-吡唑并[3,4-d]嘧啶-3-基)呋喃-2-甲醛;和/或它们的对映异构体、对映异构体的混合物、两种或更多种非对映异构体的混合物、同位素变体、药学上可接受的盐、溶剂化物、水合物或前药。
- 根据权利要求1-72中任一项所述的药物组合,其中所述PI3K抑制剂包括:2-(1-(9H-嘌呤-6-基氨基)丙基)-3-(3-氟苯基)-4H-色烯-4-酮,或其对映异构体、对映异构体的混合物、 两种或更多种非对映异构体的混合物、或同位素变体;或其药学上可接受的盐、溶剂化物、水合物或前药。
- 根据权利要求1-73中任一项所述的药物组合,其中所述PI3K抑制剂包括(S)-2-(1-(9H-嘌呤-6-基氨基)丙基)-3-(3-氟苯基)-4H-色烯-4-酮或其药学上可接受的盐、溶剂化物、水合物或前药。
- 根据权利要求1-74中任一项所述的药物组合,其包括PD-L1/TGFβ双重抑制剂和PI3K抑制剂。
- 根据权利要求75中任一项所述的药物组合,其中所述PD-L1/TGFβ双重抑制剂包含抗PD-L1抗体或其抗原结合片段和TGFβRII或其功能活性片段。
- 根据权利要求76中任一项所述的药物组合,其中所述PD-L1/TGFβ双重抑制剂包含2条多肽,所述多肽包含选自下组的氨基酸序列:(a)SEQ ID NO:7所示的氨基酸序列;(b)具有与SEQ ID NO:7所示的氨基酸序列至少85%,90%,95%或者99%序列同一性的氨基酸序列;(c)通过加成、消除或取代反应所得到的与SEQ ID NO:7所示的氨基酸序列具有1个或更多差异的氨基酸序列。
- 根据权利要求75所述的药物组合,其中所述PI3K抑制剂为PI3Kδ/γ双重抑制剂。
- 根据权利要求78所述的药物组合,其中所述PI3K抑制剂为(S)-2-(1-(9H-嘌呤-6-基氨基)丙基)-3-(3-氟苯基)-4H-色烯-4-酮或其药学上可接受的盐、溶剂化物、水合物或前药。
- 根据权利要求1-79中任一项所述的药物组合,所述第二治疗剂与所述PI3K抑制剂在所述药物组合中不互相混合。
- 根据权利要求1-80中任一项所述的药物组合,所述第二治疗剂与所述PI3K抑制剂各自独立地存在于单独的容器中。
- 根据权利要求1-81中任一项所述的药物组合,所述的药物组合还可以进一步地包括第三活性物质。
- 根据权利要求82所述的药物组合,所述的第三活性物质可以选自长春新碱、长春碱、长春地辛、依托泊苷、多西他赛、紫杉醇、伊立替康、长春瑞滨、米托蒽醌、长春氟宁、拓扑替康中的任意一种或其任意地组合。
- 药物组合物,所述药物组合包括权利要求1-83中任一项所述的PI3K抑制剂和第二治疗剂,以及任选的一种或多种药学上可接受的载体或赋形剂。
- 根据权利要求84所述的药物组合物,其中所述第二治疗剂为权利要求46-60中任一项所述的PD-L1/TGFβ双重抑制剂。
- 根据权利要求84-85中任一项所述的药物组合物,其中所述PI3K抑制剂为权利要求61-74中任一项所述的PI3Kδ/γ双重抑制剂。
- 根据权利要求84-86中任一项所述的药物组合物,其中所述第二治疗剂与所述PI3K抑制剂存在于单一或分开的剂型中。
- 一种治疗和/或预防肿瘤的方法,其包括向有需要的受试者施用:有效量的权利要求1-83中任一项所述的药物组合,或权利要求84-87中任一项所述的药物组合物。
- 根据权利要求88所述的方法,其包括向有需要的受试者施用:有效量的权利要求61-74中任一项所述的PI3K抑制剂;以及权利要求46-60中任一项所述的PD-L1/TGFβ双重抑制剂。
- 根据权利要求89所述的方法,其中所述PI3K抑制剂与所述PD-L1/TGFβ双重抑制剂同时施用。
- 根据权利要求90所述的方法,其中所述PI3K抑制剂在所述PD-L1/TGFβ双重抑制剂之后施用。
- 根据权利要求89所述的方法,其中所述PI3K抑制剂在所述PD-L1/TGFβ双重抑制剂之前施用。
- 根据权利要求89所述的方法,还包括向有需要的受试者施用有效量的权利要求41所述的小分子TGFβ抑制剂。
- 根据权利要求88-93中任一项所述的方法,其中所述肿瘤包括实体瘤和非实体瘤。
- 根据权利要求88-94中任一项所述的方法,其中所述肿瘤包括PI3K表达异常的肿瘤。
- 根据权利要求88-95中任一项所述的方法,其中所述肿瘤包括PD-L1表达异常的肿瘤。
- 根据权利要求88-96中任一项所述的方法,其中所述肿瘤包括TGFβ表达异常的肿瘤。
- 根据权利要求88-97中任一项所述的方法,所述肿瘤包括消化道肿瘤、黑素瘤或淋巴瘤。
- 权利要求1-83中任一项所述的药物组合或权利要求84-87中任一项所述的药物组合物在制备用于治疗和/或预防肿瘤的药物中的用途。
- 权利要求1-83中任一项所述的药物组合或权利要求84-87中任一项所述的药物组合物用于治疗和/或预防肿瘤。
- 一种抑制肿瘤生长的方法,所述方法包括使肿瘤接触权利要求1-83中任一项所述的药物组合或权利要求84-87中任一项所述的药物组合物。
- 一种抑制肿瘤生长的方法,所述方法包括使肿瘤接触权利要求61-74中任一项所述 的PI3K抑制剂与权利要求46-60中任一项所述的PD-L1/TGFβ双重抑制剂。
- 一种药盒,其包括:(1)第一容器,以及位于所述第一容器中的权利要求61-74中任一项所述的PI3K抑制剂;(2)第二容器,以及位于所述第二容器中权利要求46-60中任一项所述的PD-L1/TGFβ双重抑制剂。
- 一种药盒,其可以包括:(1)第一容器,以及位于所述第一容器中的权利要求61-74中任一项所述的PI3K抑制剂;(2)第二容器,以及位于所述第二容器中的权利要求17-29中任一项所述的免疫检查点的抑制剂或权利要求30-44中任一项所述的TGFβ抑制剂。
- 根据权利要求104所述的药盒,所述药盒还包括(3)第三容器,以及位于第三容器中的权利要求17-29中任一项所述的免疫检查点的抑制剂或权利要求30-44中任一项所述的TGFβ抑制剂,所述第三容器中的药剂与第二容器中的药剂不同。
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