posted on 2022-12-13, 12:35authored byAlexander Sokolsky, Oleg Vechorkin, Joshua R. Hummel, Evan D. Styduhar, Anlai Wang, Minh H. Nguyen, Hai Fen Ye, Kai Liu, Ke Zhang, Jun Pan, Qinda Ye, Onur Atasoylu, Elham Behshad, Xin He, Patricia Conlen, Kristine Stump, Min Ye, Sharon Diamond, Maryanne Covington, Swamy Yeleswaram, Wenqing Yao
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.