Discovery of 1(2H)-phthalazinone and 1(2H)-isoquinolinone derivatives as potent hematopoietic progenitor kinase 1 (HPK1) inhibitors.

Although immune checkpoint inhibitors (ICIs) have been a revelation for treating several cancers, an unmet need remains to broaden ICI therapeutic scope and increase their response rates in clinical trials. Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of T cell activation and has previously been identified as a promising target for immunotherapy. Herein, we report the discovery of a series of HPK1 inhibitors with novel 1(2H)-phthalazinone and 1(2H)-isoquinolinone scaffolds. Among them, compound 24 demonstrated potent in vitro activity (HPK1 IC ₅₀ value of 10.4 nM) and cellular activity (pSLP76 EC ₅₀  = 41 nM & IL-2 EC ₅₀  = 108 nM). Compound 24 exhibited favorable mouse and rat pharmacokinetic profiles with reasonable oral exposure. Compound 24 showed potent in vivo anti-tumor activity in a CT26 syngeneic tumor model with 95 % tumor growth inhibition in combination with anti-PD-1.
Competing Interests: Declaration of competing interest We declare that no conflict of interest exists in the submission of this manuscript, and all the authors listed have approved the manuscript that is enclosed. The work described was original research that has not been published previously, and not under consideration for publication elsewhere, in whole or in part. This work is being submitted to European Journal of Medicinal Chemistry exclusively.
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