Development of a series of quinazoline-2,5-diamine derivatives as potent hematopoietic progenitor kinase 1 (HPK1) inhibitors

Authors

  • Huanyu Shi Shanghai Institute of Materia Medica, Chinese Academy of Sciences ,
  • Haotian Tang Shanghai Institute of Materia Medica, Chinese Academy of Sciences ,
  • Yan Li Shanghai Institute of Materia Medica, Chinese Academy of Sciences ,
  • Danqi Chen Shanghai Institute of Materia Medica, Chinese Academy of Sciences ,
  • Tongchao Liu Shanghai Institute of Materia Medica, Chinese Academy of Sciences ,
  • Yuting Chen Shanghai Institute of Materia Medica, Chinese Academy of Sciences ,
  • Xin Wang Shanghai Institute of Materia Medica, Chinese Academy of Sciences ,
  • Lin Chen Shanghai Institute of Materia Medica, Chinese Academy of Sciences ,
  • Ying Wang Shanghai Institute of Materia Medica, Chinese Academy of Sciences ,
  • Hua Xie Shanghai Institute of Materia Medica, Chinese Academy of Sciences ,
  • Bing Xiong Shanghai Institute of Materia Medica, Chinese Academy of Sciences

Abstract

Hematopoietic progenitor kinase 1 (HPK1) is a serine/threonine kinase that serves as the negative regulator of multiple immune signaling pathways. Genetic studies using HPK1 knockout and kinase-dead mice suggested that inhibiting HPK1 either alone or in combination with immune checkpoint blockade could be promising strategy in cancer immunotherapy. Herein, we report the design, synthesis and structure–activity relationship (SAR) study of a series of potent HPK1 inhibitors bearing quinazoline-2,5-diamine scaffold. Three rounds of SAR explorations led to the identification of 9h, the most potent compound in this series which harbors a 2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl substituent. Further biological studies using human immune cells demonstrated that 9h could strongly inhibit the downstream phosphorylation, augment the IL-2 secretion and reverse the PGE2-induced immune suppression. Overall, 9h can serve as a tool compound to help with demonstrating the pharmacological role of HPK1 kinase inhibition, and our investigation provided a reliable reference for the later development of HPK1 inhibitors.

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