Discovery of 1,2,4-benzotriazine derivatives as new hematopoietic progenitor kinase 1 (HPK1) inhibitors

Bioorganic Chemistry, Journal Year: 2025, Volume and Issue: 156, P. 108158 - 108158

Published: Jan. 10, 2025

Language: Английский

Discovery and Optimization of Pyrazine Carboxamide AZ3246, a Selective HPK1 Inhibitor

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 10, 2025

Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of the T cell receptor signaling pathway and therefore target interest for immunooncology. Nonselective HPK1 inhibitors may affect other components activation, blunting beneficial impact enhanced activity that results from inhibition itself. Here, we report discovery pyrazine carboxamide their optimization through structure-based drug design to afford highly selective inhibitor, compound 24 (AZ3246). This induces IL-2 secretion in cells with an EC50 90 nM without inhibiting antagonistic kinases, exhibits pharmacokinetic properties consistent oral dosing, demonstrates antitumor EMT6 syngeneic mouse model.

Language: Английский

Design, synthesis, and biological evaluation of 2,4-diaminopyrimidine inhibitors of hematopoietic progenitor kinase 1

Bioorganic & Medicinal Chemistry Letters, Journal Year: 2025, Volume and Issue: unknown, P. 130242 - 130242

Published: April 1, 2025

Language: Английский