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.

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