Discovery of Spiro-azaindoline Inhibitors of Hematopoietic Progenitor Kinase 1 (HPK1)

ACS Med Chem Lett. 2021 Dec 8;13(1):84-91. doi: 10.1021/acsmedchemlett.1c00473.

Bryan K Chan ¹, Eileen Seward ², Michael Lainchbury ², Thomas F Brewer ¹, Le An ¹, Toby Blench ², Matthew W Cartwright ², Grace Ka Yan Chan ¹, Edna F Choo ¹, Jason Drummond ¹, Richard L Elliott ², Emanuela Gancia ², Lewis Gazzard ¹, Baihua Hu ³, Graham E Jones ², Xifeng Luo ³, Andrew Madin ², Sushant Malhotra ¹, John G Moffat ¹, Jodie Pang ¹, Laurent Salphati ¹, Christopher J Sneeringer ¹, Craig E Stivala ¹, Binqing Wei ¹, Weiru Wang ¹, Ping Wu ¹, Timothy P Heffron ¹

Affiliations

1 Genentech Inc., 1 DNA Way, South San Francisco, California 94080, United States.
2 Charles River Laboratories, 8-9 Spire Green, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom.
3 Pharmaron Beijing Co, No. 6 Tai He Road, BDA, Beijing 100176, P.R. China.

PMID: 35059127 DOI: 10.1021/acsmedchemlett.1c00473

Abstract

Hematopoietic progenitor kinase 1 (HPK1) is implicated as a negative regulator of T-cell receptor-induced T-cell activation. Studies using HPK1 kinase-dead knock-in Animals have demonstrated the loss of HPK1 kinase activity resulted in an increase in T-cell function and tumor growth inhibition in glioma models. Herein, we describe the discovery of a series of small molecule inhibitors of HPK1. Using a structure-based drug design approach, the kinase selectivity of the molecules was significantly improved by inducing and stabilizing an unusual P-loop folded binding mode. The metabolic liabilities of the initial 7-azaindole high-throughput screening hit were mitigated by addressing a key metabolic soft spot along with physicochemical property-based optimization. The resulting spiro-azaindoline HPK1 inhibitors demonstrated improved in vitro ADME properties and the ability to induce cytokine production in primary human T-cells.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-144073

HPK1-IN-21

HPK1 Kinase Inhibitor

MAP4K

Cancer

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