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US-12617811-B2 - HPK1 inhibitors and uses thereof

US12617811B2US 12617811 B2US12617811 B2US 12617811B2US-12617811-B2

Abstract

The invention provides a compound represented by structural formula (I) or formula (II), or a pharmaceutically acceptable salt or a stereoisomer thereof useful for treating diseases (such as cancer) that are treatable by inhibiting HPK1 activity.

Inventors

  • Wenge Zhong
  • Xiaotian Zhu
  • Song Feng
  • Lei Wu
  • Wei Huang
  • Hao Liu
  • Rongqiang LIU
  • Kate Xin Wen
  • Hua Zhou

Assignees

  • REGOR PHARMACEUTICALS, INC.

Dates

Publication Date
20260505
Application Date
20210702
Priority Date
20200703

Claims (20)

  1. 1 . A compound represented by Formula I, or a pharmaceutically acceptable salt, or a stereoisomer thereof.
  2. 2 . The compound of claim 1 , represented by Formula IA, or a pharmaceutically acceptable salt.
  3. 3 . Ne compound of claim 1 , represented by Formula IB, or a pharmaceutically acceptable salt.
  4. 4 . A compound represented by Formula IIA, or a pharmaceutically acceptable salt.
  5. 5 . A compound represented by Formula IIB, or a pharmaceutically acceptable salt.
  6. 6 . A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt or a stereoisomer thereof, and a pharmaceutically acceptable carrier.
  7. 7 . A combination comprising a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, and one or more therapeutically active co-agents.
  8. 8 . A method for treating a subject with cancer, comprising administering to the subject an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, or a stereoisomer thereof.
  9. 9 . The method of claim 8 , wherein the cancer is selected from breast cancer, colorectal cancer, lung cancer, ovarian cancer, and pancreatic cancer.
  10. 10 . A method of inhibiting HPK1 activity in a subject in need thereof, said method comprising administering to the subject an effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof.
  11. 11 . The method of claim 10 , wherein the subject has a cancer, and wherein the cancer is treated.
  12. 12 . The method of claim 11 , wherein the cancer is selected from breast cancer, colorectal cancer, lung cancer, ovarian cancer, and pancreatic cancer.
  13. 13 . A method for treating a subject with cancer, comprising administering to the subject a therapeutically effective amount of the compound of claim 1 in combination with an immune checkpoint inhibitor, wherein the immune checkpoint inhibitor is a PD-1 inhibitor, a PD-L1 inhibitor, or a CTLA-4 inhibitor.
  14. 14 . The method of claim 13 , wherein the immune checkpoint inhibitor is a bispecific monoclonal antibody or an antigen binding fragment thereof specific for PD-1 and PD-L1, or CTLA-4.
  15. 15 . The method of claim 14 , wherein the cancer is selected from breast cancer, colorectal cancer, lung cancer, ovarian cancer, and pancreatic cancer.
  16. 16 . A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 5 or a pharmaceutically acceptable salt or a stereoisomer thereof, and a pharmaceutically acceptable carrier.
  17. 17 . A combination comprising a therapeutically effective amount of the compound of claim 5 or a pharmaceutically acceptable salt or a stereoisomer thereof, and one or more therapeutically active co-agents.
  18. 18 . A method for treating a subject with cancer, comprising administering to the subject an effective amount of a compound of claim 5 , or a pharmaceutically acceptable salt, or a stereoisomer thereof.
  19. 19 . The method of claim 18 , wherein the cancer is selected from breast cancer, colorectal cancer, lung cancer, ovarian cancer, and pancreatic cancer.
  20. 20 . A method of inhibiting HPK1 activity in a subject in need thereof, said method comprising administering to the subject an effective amount of compound of claim 5 , or a pharmaceutically acceptable salt or a stereoisomer thereof.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a 35 U.S.C. § 371 national stage filing of International Application No. PCT/CN2021/104206 filed on Jul. 2, 2021, which claims the benefit of International Patent Application No. PCT/CN2020/100134, filed on Jul. 3, 2020. The entire contents of each of the aforementioned applications are incorporated herein by reference. BACKGROUND OF THE INVENTION Hematopoietic Progenitor Kinase 1 (HPK1), also known as Mitogen-Activated Protein Kinase Kinase Kinase Kinase 1 (MAP4K1), is a protein kinase that acts upstream of the classic 3-tiered MAPK pathway that includes MAP3K (MAP Kinase Kinase Kinase), which activates MAP2K (MAP Kinase Kinase), which in turn activates the dual Thr and Tyr MAPK family member JNK (c-Jun N-terminal kinase). Originally cloned in hematopoietic progenitor cells, HPK1/MAP4K1 is predominantly expressed in lymphoid organs/tissues, including the bone marrow, fetal liver, lymph node, placenta, spleen, and thymus (Hu et al., Gene & Dev. 10(18): 2251-2264, 1996; Kiefer et al., The EMBO J. 15(24): 7013-7025, 1996). At the cellular level, HPK1 is expressed in all cell types in the hematopoietic compartment, including hematopoietic progenitor cells, T cells, B cells, macrophages, dendritic cells, neutrophils, and mast cells (Hu, supra; Kiefer, supra). HPK1/MAP4K1 is one of the six MAP4Ks that include HPK1 (MAP4K1), GCK (MAP4K2), GLK (MAP4K3), HGK/NIK (MAP4K4), KHS/GCKR (MAP4K5), and MINK (MAP4K6). Together, these MAP4Ks are members of about 26 mammalian Ste20-like serine/threonine kinases identified so far, which are homologs of the yeast sterile20 protein (Ste20p), a putative MAP4K that activates a MAP3K in the yeast pheromone signaling pathway. These mammalian Ste20-like kinases are divided into two subfamilies based on the domain structures: the p21-activated kinases (PAKs) and the germinal center kinases (GCKs). Among the GCK subfamily, several of them can activate the MAP3K kinase cascade, leading to JNK activation. The MAP4Ks are highly similar structurally, with an N-terminal kinase domain (KD), followed by 2-4 proline-rich motifs, and a C-terminal citron-homology domain (CNH). The ATP-binding site of the kinase domain of HPK1 includes Lys-46. Mutation of this residue to Met (HPK1-M46) abolishes catalytic activation of HPK1 (Hu, supra). There are multiple conserved Ser/Thr phosphorylation sites within the kinase domain of HPK1, and a conserved Tyr phosphorylation site between its first two proline-rich motifs. Phosphorylation of Tyr379 (in mouse, or Tyr381 in human) by LCK/ZAP70 appears to be required for HPK1 activation, since the deficiency of LCK or ZAP70 abolishes Tyr-379 phosphorylation and kinase activity of HPK1 in Jurkat T cells upon anti-CD3 stimulation (Ling et al., JBC 276(22):18908-18914, 2001; Liou et al., Immunity 12(4):399-408, 2000; Sauer et al., JBC 276(48):45207, 45216, 2001). On the other hand, Thr-355 autophosphorylation regulates ubiquitination and degradation of HPK1. Thr-355 is a PP4-targeted dephosphorylation site; this dephosphorylation prevents CUL7/Fbxw8-mediated ubiquitination and proteasomal degradation of activated HPK1 (Wang et al., Cancer Res. 69(3):1063-1070, 2009), thus HPK1 is also stabilized and activated by protein phosphatase 4 (PP4) (Zhou et al., JBC 279(47):49551-49561, 2004). The Tyr phosphorylation site is also adjacent to a caspase cleavage site (DDVD). It has been shown that the full-length HPK1 can be cleaved by caspase-3 at this site in apoptotic cells, resulting in an enhanced catalytic activity of the N-terminal HPK1 fragment (Chen et al., Oncogene 18:7370-7377, 1999). The four Pro-rich motifs of HPK1 mediate the interaction of HPK1 with many SH3 domain-containing proteins (Boomer & Tan, JCB 95(1): 34-44, 2005). The CNH domain of HPK1 may be involved in HPK1-mediated lymphocyte adhesion because the citron homology domain in another Ste20-like kinase TNIK binds to Rap2 and regulates actin cytoskeleton (Taira et al., JBC 279(47):49488-49496, 2004). The MAP4Ks play important roles in the immune system, particularly in lymphocytes, through regulating cellular signaling, immune cell activation, cell transformation, and cell migration. HPK1 knock-out (KO) mice show enhanced T-cell activation, increased cytokine production, and increased antibody production after KLH immunization. HPK1 KO mice are also more susceptible to EAE induction. HPK1 KO T cells and B cells show enhanced cell activation and antigen receptor signaling. HPK1 KO dendritic cells show higher levels of co-stimulating molecules and proinflammatory cytokines (Alzabin et al., J. Immunol. 182(10):6187-6194, 2009; Shui et al., Nat. Immunol. 8(1):84-91, 2007). Overexpression in cell lines (e.g., HEK293 and COS-1 cells, and hematopoietic Jurkat T cells and leukemia HL-60 cells) demonstrated that HPK1 can activate the MAPK JNK (but not p38 or ERK MAP kinases) through multiple MAP3Ks (including TAK1, MEKK1, and MLK3), which all activate M