Dataset Information

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.

SUBMITTER: Chan BK

PROVIDER: S-EPMC8762754 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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

Chan Bryan K BK Seward Eileen E Lainchbury Michael M Brewer Thomas F TF An Le L Blench Toby T Cartwright Matthew W MW Chan Grace Ka Yan GKY Choo Edna F EF Drummond Jason J Elliott Richard L RL Gancia Emanuela E Gazzard Lewis L Hu Baihua B Jones Graham E GE Luo Xifeng X Madin Andrew A Malhotra Sushant S Moffat John G JG Pang Jodie J Salphati Laurent L Sneeringer Christopher J CJ Stivala Craig E CE Wei Binqing B Wang Weiru W Wu Ping P Heffron Timothy P TP

ACS medicinal chemistry letters 20211208 1

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 ...[more]

PMID: 35059127

Dataset Information

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

Publications

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

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