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

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.

• Authors: Bryan K Chan, Eileen Seward, Michael Lainchbury, Thomas F Brewer, Le An, Toby Blench, Matthew W Cartwright, Grace Ka Yan Chan, Edna F Choo, Jason Drummond, Richard L Elliott, Emanuela Gancia, Lewis Gazzard, Baihua Hu, Graham E Jones, Xifeng Luo, Andrew Madin, Sushant Malhotra, John G Moffat, Jodie Pang, Laurent Salphati, Christopher J Sneeringer, Craig E Stivala, Binqing Wei, Weiru Wang, Ping Wu, Timothy P Heffron
• Journal: ACS medicinal chemistry letters (ACS Med Chem Lett) Vol. 13 Issue 1 Pg. 84-91 (Jan 13 2022) ISSN: 1948-5875 [Print] United States
• PMID: 35059127 (Publication Type: Journal Article)
• Copyright: © 2021 American Chemical Society.