Potent and Selective Biaryl Amide Inhibitors of Hematopoietic Progenitor Kinase 1 (HPK1).
Alexander SokolskyOleg VechorkinJoshua R HummelEvan D StyduharAnlai WangMinh H NguyenHai Fen YeKai LiuKe ZhangJun PanQinda YeOnur AtasoyluElham BehshadXin HePatricia ConlenKristine StumpMin YeSharon DiamondMaryanne CovingtonSwamy YeleswaramWenqing YaoPublished in: ACS medicinal chemistry letters (2022)
Herein we report the discovery of a novel biaryl amide series as selective inhibitors of hematopoietic protein kinase 1 (HPK1). Structure-activity relationship development, aided by molecular modeling, identified indazole 5b as a core for further exploration because of its outstanding enzymatic and cellular potency coupled with encouraging kinome selectivity. Late-stage manipulation of the right-hand aryl and amine moieties surmounted issues of selectivity over TRKA, MAP4K2, and STK4 as well as generating compounds with balanced in vitro ADME profiles and promising pharmacokinetics.