期刊
ACS MEDICINAL CHEMISTRY LETTERS
卷 14, 期 1, 页码 116-122出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.2c00241
关键词
HPK1; tyrosine kinase inhibition; selectivity profile; STK4
A novel biaryl amide series has been discovered as selective inhibitors of HPK1, showing outstanding enzymatic and cellular potency and encouraging kinome selectivity.
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.
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