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Potent and Selective Biaryl Amide Inhibitors of Hematopoietic Progenitor Kinase 1 (HPK1).

ABSTRACT: 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.

SUBMITTER: Sokolsky A

PROVIDER: S-EPMC9841582 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Potent and Selective Biaryl Amide Inhibitors of Hematopoietic Progenitor Kinase 1 (HPK1).

Sokolsky Alexander A Vechorkin Oleg O Hummel Joshua R JR Styduhar Evan D ED Wang Anlai A Nguyen Minh H MH Ye Hai Fen HF Liu Kai K Zhang Ke K Pan Jun J Ye Qinda Q Atasoylu Onur O Behshad Elham E He Xin X Conlen Patricia P Stump Kristine K Ye Min M Diamond Sharon S Covington Maryanne M Yeleswaram Swamy S Yao Wenqing W

ACS medicinal chemistry letters 20221213 1

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 <b>5b</b> 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 w ...[more]

PMID: 36655134

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