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

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 a 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 exploration 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 assessments using human immune cells demonstrated that 9h could strongly inhibit downstream phosphorylation, augment interleukin-2 (IL-2) pro-duction and reverse prostaglandin E2 (PGE2)-induced immune suppression. Overall, our study on these quinazoline-2,5-diamine derivatives provided not only a tool compound for the community to help with eluci-dating the HPK1 pharmacology, but also a reliable reference for subsequent development of HPK1 inhibitors.

Automated summary

In this study, a series of potent HPK1 inhibitors with quinazoline-2,5-diamine scaffold were designed, synthesized and evaluated. The most potent compound 9h was identified, which exhibited strong inhibition of downstream phosphorylation, enhanced interleukin-2 (IL-2) production, and reversed prostaglandin E2 (PGE2)-induced immune suppression. This research not only provided a tool compound for studying HPK1 pharmacology, but also served as a reliable reference for the development of HPK1 inhibitors.