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. 2022 Dec 13;14(1):116-122.
doi: 10.1021/acsmedchemlett.2c00241. eCollection 2023 Jan 12.

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

Alexander Sokolsky  1 , Oleg Vechorkin  1 , Joshua R Hummel  1 , Evan D Styduhar  1 , Anlai Wang  1 , Minh H Nguyen  1 , Hai Fen Ye  1 , Kai Liu  1 , Ke Zhang  1 , Jun Pan  1 , Qinda Ye  1 , Onur Atasoylu  1 , Elham Behshad  1 , Xin He  1 , Patricia Conlen  1 , Kristine Stump  1 , Min Ye  1 , Sharon Diamond  1 , Maryanne Covington  1 , Swamy Yeleswaram  1 , Wenqing Yao  1
Affiliations

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

Alexander Sokolsky et al. ACS Med Chem Lett. .

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.

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Conflict of interest statement

The authors declare the following competing financial interest(s): All of the authors are current or former employees of Incyte Corporation.

Figures

Figure 1
Figure 1
Scaffold hop from 1H-pyrazolo[3,4-c]pyridine to a picolinamide-based core.
Figure 2
Figure 2
(A) Docking model of compound 2 in complex with HPK1. The R isomer is shown. Color coding: green, P-loop; yellow, hinge; red, catalytic loop. (B) Overlay of compounds 1 (magenta) and (R)-2 (cyan).
See this image and copyright information in PMC

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