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

被引：7

作者：

Sokolsky, Alexander ^{[1
]}

Vechorkin, Oleg ^{[1
]}

Hummel, Joshua R. ^{[1
]}

Styduhar, Evan D. ^{[1
]}

Wang, Anlai ^{[1
]}

Nguyen, Minh H. ^{[1
]}

Ye, Hai Fen ^{[1
]}

Liu, Kai ^{[1
]}

Zhang, Ke ^{[1
]}

Pan, Jun ^{[1
]}

Ye, Qinda ^{[1
]}

Atasoylu, Onur ^{[1
]}

Behshad, Elham ^{[1
]}

He, Xin ^{[1
]}

Conlen, Patricia ^{[1
]}

Stump, Kristine ^{[1
]}

Ye, Min ^{[1
]}

Diamond, Sharon ^{[1
]}

Covington, Maryanne ^{[1
]}

Yeleswaram, Swamy ^{[1
]}

Yao, Wenqing ^{[1
]}

机构：

[1] Incyte Res Inst, Wilmington, DE 19803 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2023年 / 14卷 / 01期

关键词：

HPK1; tyrosine kinase inhibition; selectivity profile; STK4; TARGET; IMMUNOLOGY; IMMUNITY;

D O I：

10.1021/acsmedchemlett.2c00241

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：116 / 122

页数：7

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