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Future medicinal chemistry
2024;16 (22): 2431-2450.

An updated review of small-molecule HPK1 kinase inhibitors (2016-present).

Yiping Duan, Zhichao Guo, Wenyi Zhong, Jichao Chen, Shengtao Xu, Jie Liu, Jinyi Xu
Author Information
  1. Yiping Duan: Department of Medicinal Chemistry, China Pharmaceutical University, School of Pharmacy, Nanjing, Jiangsu, 211198, Peoples Republic China. ORCID
  2. Zhichao Guo: Department of Medicinal Chemistry, China Pharmaceutical University, School of Pharmacy, Nanjing, Jiangsu, 211198, Peoples Republic China.
  3. Wenyi Zhong: Department of Organic Chemistry, China Pharmaceutical University, School of Science, Nanjing, Jiangsu, 211198, Peoples Republic China.
  4. Jichao Chen: Nanjing University Chinese Medicine, School of Pharmacy, Nanjing, Jiangsu, 210023, Peoples Republic China.
  5. Shengtao Xu: Department of Medicinal Chemistry, China Pharmaceutical University, School of Pharmacy, Nanjing, Jiangsu, 211198, Peoples Republic China. ORCID
  6. Jie Liu: Department of Organic Chemistry, China Pharmaceutical University, School of Science, Nanjing, Jiangsu, 211198, Peoples Republic China. ORCID
  7. Jinyi Xu: Department of Medicinal Chemistry, China Pharmaceutical University, School of Pharmacy, Nanjing, Jiangsu, 211198, Peoples Republic China. ORCID
PMID: 39582317 DOI: 10.1080/17568919.2024.2420630

Abstract

Hematopoietic progenitor kinase 1 (HPK1) is a serine-threonine kinase specific to hematopoiesis and a member of the MAP4K family of Ste20-related protein kinases. Targeting HPK1 to ameliorate T cell exhaustion and enhance T cell functions is a promising strategy for clinical immunotherapies. Numerous studies have reported the progress in developing effective HPK1 inhibitors and elucidating their mechanisms of action. However, most inhibitors affect multiple signaling pathways, resulting in unintended side effects that limit their clinical development and application. Herein, we reviewed HPK1-related signaling pathways, clinical candidates and recent advances in small-molecule inhibitors targeting HPK1. Additionally, we present our perspectives on current challenges and potential future research field, hoping to provide inspiration for the development of novel HPK1 inhibitors.

Keywords

HPK1 inhibitor T cell exhaustion anti-tumor immunotherapy small-molecule inhibitors

References

  1. PLoS One. 2019 Mar 26;14(3):e0212670 [PMID: 30913212]
  2. Oncotarget. 2016 Aug 9;7(32):52575-52583 [PMID: 27270649]
  3. Eur J Med Chem. 2022 Dec 15;244:114819 [PMID: 36209628]
  4. J Autoimmun. 2011 Nov;37(3):180-9 [PMID: 22014533]
  5. J Biol Chem. 2004 Nov 19;279(47):49551-61 [PMID: 15364934]
  6. Expert Opin Ther Targets. 2024 Apr;28(4):237-250 [PMID: 38650383]
  7. EMBO J. 1996 Dec 16;15(24):7026-35 [PMID: 9003778]
  8. Science. 2016 Dec 2;354(6316):1160-1165 [PMID: 27789795]
  9. J Biol Chem. 2019 Jun 7;294(23):9029-9036 [PMID: 31018963]
  10. Bioorg Chem. 2023 Oct;139:106728 [PMID: 37536217]
  11. ACS Med Chem Lett. 2021 Dec 08;13(1):84-91 [PMID: 35059127]
  12. J Immunol. 2000 Aug 1;165(3):1417-26 [PMID: 10903746]
  13. J Clin Oncol. 2013 Mar 10;31(8):1105-11 [PMID: 23401436]
  14. Oncotarget. 2017 Apr 18;8(16):26702-26717 [PMID: 28460458]
  15. Eur J Med Chem. 2023 Feb 15;248:115064 [PMID: 36621137]
  16. Bioorg Med Chem. 2023 Sep 7;92:117423 [PMID: 37531921]
  17. Bioorg Chem. 2024 Feb;143:107016 [PMID: 38086239]
  18. Clin Breast Cancer. 2021 Feb;21(1):e63-e73 [PMID: 32893093]
  19. J Clin Oncol. 2015 Dec 10;33(35):4210-8 [PMID: 26371140]
  20. Cancer Lett. 2021 May 28;506:55-66 [PMID: 33662493]
  21. J Epidemiol Glob Health. 2019 Dec;9(4):217-222 [PMID: 31854162]
  22. J Immunother. 2005 Mar-Apr;28(2):120-8 [PMID: 15725955]
  23. Cancer Immunol Res. 2019 Mar;7(3):363-375 [PMID: 30651290]
  24. Eur J Med Chem. 2024 Mar 5;267:116206 [PMID: 38350360]
  25. Mol Med Rep. 2017 Nov;16(5):6472-6482 [PMID: 28901492]
  26. Eur J Med Chem. 2023 Jun 5;254:115355 [PMID: 37062169]
  27. Structure. 2019 Jan 2;27(1):125-133.e4 [PMID: 30503777]
  28. J Med Chem. 2023 Dec 14;66(23):16201-16221 [PMID: 37990878]
  29. ACS Med Chem Lett. 2021 Mar 19;12(4):653-661 [PMID: 33859804]
  30. Front Immunol. 2019 Jul 25;10:1704 [PMID: 31402911]
  31. Cancer Lett. 2016 Jan 1;370(1):153-64 [PMID: 26499806]
  32. ACS Med Chem Lett. 2022 Dec 13;14(1):116-122 [PMID: 36655134]
  33. Blood. 2024 Mar 7;143(10):840-841 [PMID: 38451513]
  34. Bioorg Chem. 2023 Sep;138:106682 [PMID: 37339563]
  35. Mol Med. 2004 Jul-Dec;10(7-12):96-103 [PMID: 16113842]
  36. J Med Chem. 2023 Apr 13;66(7):4888-4909 [PMID: 36940470]
  37. Immunity. 2020 Sep 15;53(3):658-671.e6 [PMID: 32937153]
  38. Adv Immunol. 2016;129:277-314 [PMID: 26791862]
  39. Biochemistry. 2021 Oct 19;60(41):3114-3124 [PMID: 34608799]
  40. Nat Commun. 2024 May 2;15(1):3725 [PMID: 38697971]
  41. Nat Commun. 2020 Apr 24;11(1):2011 [PMID: 32332714]
  42. Oncogene. 1999 Sep 30;18(40):5514-24 [PMID: 10523828]
  43. EBioMedicine. 2018 Oct;36:553-562 [PMID: 30224312]
  44. Expert Opin Pharmacother. 2014 Feb;15(2):283-97 [PMID: 24328549]
  45. J Biol Chem. 2004 Jul 2;279(27):28724-32 [PMID: 15100220]
  46. J Cell Biol. 2011 Nov 28;195(5):839-53 [PMID: 22105350]
  47. Cancer Immunol Immunother. 2010 Mar;59(3):419-29 [PMID: 19787351]
  48. J Biol Chem. 2012 Mar 30;287(14):11037-48 [PMID: 22334673]
  49. ACS Med Chem Lett. 2022 Dec 12;14(1):5-10 [PMID: 36655125]
  50. Semin Cancer Biol. 2020 Dec;67(Pt 2):171-179 [PMID: 32058059]
  51. Expert Opin Ther Pat. 2021 Oct;31(10):893-910 [PMID: 33956554]
  52. Front Pharmacol. 2022 Mar 14;13:850855 [PMID: 35370676]
  53. Nat Biotechnol. 2011 Oct 30;29(11):1046-51 [PMID: 22037378]
  54. J Biol Chem. 2001 Jun 1;276(22):18908-14 [PMID: 11279207]
  55. Nat Immunol. 2007 Jan;8(1):84-91 [PMID: 17115060]
  56. J Biol Chem. 2001 May 4;276(18):14675-84 [PMID: 11278403]
  57. Mol Cell Biol. 1999 Feb;19(2):1359-68 [PMID: 9891069]
  58. Pharmacol Res. 2023 May;191:106774 [PMID: 37075870]
  59. Expert Opin Investig Drugs. 2016;25(1):31-49 [PMID: 26560489]
  60. Ann Agric Environ Med. 2021 Mar 18;28(1):11-19 [PMID: 33775063]
  61. Elife. 2020 Sep 08;9: [PMID: 32896273]
  62. Mol Cancer. 2017 Mar 21;16(1):67 [PMID: 28327152]
  63. Expert Rev Anticancer Ther. 2015 Jun;15(6):677-87 [PMID: 25936222]
  64. ADMET DMPK. 2021 Aug 31;9(4):243-254 [PMID: 35300370]
  65. Int J Mol Sci. 2023 Jan 31;24(3): [PMID: 36768974]
  66. Eur J Pharmacol. 2023 Dec 15;961:176184 [PMID: 37944847]
  67. J Med Chem. 2022 Jun 23;65(12):8065-8090 [PMID: 35696642]
  68. Front Immunol. 2013 Jul 25;4:212 [PMID: 23898333]
  69. PLoS One. 2020 Dec 3;15(12):e0243145 [PMID: 33270695]
  70. Med Res Rev. 2021 Jan;41(1):525-555 [PMID: 33047304]
  71. Daru. 2021 Dec;29(2):397-414 [PMID: 34216003]
  72. ACS Chem Biol. 2022 Mar 18;17(3):556-566 [PMID: 35188729]
  73. PLoS One. 2017 Jan 20;12(1):e0170396 [PMID: 28107427]
  74. Lancet. 2015 Apr 11;385(9976):1447-59 [PMID: 25484026]
  75. J Biol Chem. 2012 Oct 5;287(41):34091-100 [PMID: 22902619]
  76. Immunity. 2000 Apr;12(4):399-408 [PMID: 10795738]
  77. Eur J Med Chem. 2024 Apr 5;269:116310 [PMID: 38479166]
  78. Ann Oncol. 2020 Sep;31(9):1148-1159 [PMID: 32569725]
  79. Blood. 2003 May 1;101(9):3687-9 [PMID: 12522005]
  80. Acta Crystallogr F Struct Biol Commun. 2021 Jan 1;77(Pt 1):22-28 [PMID: 33439152]
  81. Nat Genet. 2019 Dec;51(12):1732-1740 [PMID: 31740835]
  82. Cell Signal. 2022 Nov;99:110446 [PMID: 35995302]
  83. J Biol Chem. 2007 Nov 30;282(48):34693-9 [PMID: 17895239]
  84. Cell. 2020 Apr 2;181(1):102-114 [PMID: 31955850]
  85. Oncogene. 1998 Oct 15;17(15):1893-901 [PMID: 9788432]
  86. ACS Med Chem Lett. 2021 Feb 19;12(3):443-450 [PMID: 33732413]
  87. EMBO J. 2005 Dec 21;24(24):4279-90 [PMID: 16341093]
  88. Bioorg Chem. 2023 Nov;140:106811 [PMID: 37659145]
  89. J Med Chem. 2018 Jun 14;61(11):4851-4859 [PMID: 29746776]
  90. J Med Chem. 2023 Jan 12;66(1):611-626 [PMID: 36542759]
  91. J Immunol. 2009 May 15;182(10):6187-94 [PMID: 19414772]
  92. ACS Med Chem Lett. 2021 Mar 01;12(3):459-466 [PMID: 33738073]
  93. Nat Med. 2016 Dec;22(12):1402-1410 [PMID: 27775706]
  94. EMBO J. 1996 Dec 16;15(24):7013-25 [PMID: 9003777]
  95. Immunol Res. 2012 Dec;54(1-3):262-5 [PMID: 22477524]

Grants

  1. No. 82173679, 81973167, 82304285/National Natural Science Foundation of China
  2. CPUQNJC22/"Double First-Class" University project of China Pharmaceutical University

MeSH Term

Humans
Protein Kinase Inhibitors
Protein Serine-Threonine Kinases
Small Molecule Libraries
Signal Transduction
Animals

Chemicals

Protein Kinase Inhibitors
Protein Serine-Threonine Kinases
hematopoietic progenitor kinase 1
Small Molecule Libraries
Journal Article Review

Word Cloud

Created with Highcharts 10.0.0HPK1inhibitorskinaseTcellclinicalsmall-moleculeexhaustionsignalingpathwaysdevelopmentHematopoieticprogenitor1serine-threoninespecifichematopoiesismemberMAP4KfamilySte20-relatedproteinkinasesTargetingameliorateenhancefunctionspromisingstrategyimmunotherapiesNumerousstudiesreportedprogressdevelopingeffectiveelucidatingmechanismsactionHoweveraffectmultipleresultingunintendedsideeffectslimitapplicationHereinreviewedHPK1-relatedcandidatesrecentadvancestargetingAdditionallypresentperspectivescurrentchallengespotentialfutureresearchfieldhopingprovideinspirationnovelupdatedreview2016-presentinhibitoranti-tumorimmunotherapy

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