2. Academic Validation
  3. Discovery of GNE-6893, a Potent, Selective, Orally Bioavailable Small Molecule Inhibitor of HPK1

Discovery of GNE-6893, a Potent, Selective, Orally Bioavailable Small Molecule Inhibitor of HPK1

  • ACS Med Chem Lett. 2024 Sep 3;15(9):1606-1614. doi: 10.1021/acsmedchemlett.4c00319.
John C Tellis 1,  BinQing Wei 1,  Michael Siu 1,  Le An 1,  Grace Kayan Chan 1,  Yong Chen 2,  Xiangnan Du 1,  Lewis Gazzard 1,  Baihua Hu 2,  James Kiefer 1,  Satoko Kakiuchi-Kiyota 1,  Michael Lainchbury 3,  Jonathan L Linehan 1,  Xifeng Luo 2,  Sushant Malhotra 1,  Rohan Mendonca 1,  Jodie Pang 1,  Yinqing Ran 1,  Vijay Sethuraman 1,  Eileen Seward 3,  Chris Sneeringer 1,  Dian Su 1,  Weiru Wang 1,  Ping Wu 1,  John G Moffat 1,  Timothy P Heffron 1,  Edna F Choo 1,  Bryan K Chan 1
Affiliations

Affiliations

  • 1 Genentech Inc., 1 DNA Way, South San Francisco, California 94080, United States.
  • 2 Pharmaron Beijing Co., No. 6 Tai He Road, BDA, Beijing 100176, P.R. China.
  • 3 Charles River Laboratories, 8-9 Spire Green, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom.
PMID: 39291002 DOI: 10.1021/acsmedchemlett.4c00319
Abstract

Hematopoietic progenitor kinase 1 (HPK1) serves a key immunosuppressive role as a negative regulator of T-cell receptor (TCR) signaling. HPK1 loss-of-function is associated with augmentation of immune function and has demonstrated synergy with immune checkpoint inhibitors in syngeneic mouse Cancer models. These data offer compelling evidence for the use of selective small molecule inhibitors of HPK1 in Cancer Immunotherapy. We identified a novel series of isoquinoline HPK1 inhibitors through fragment-based screening that displayed promising levels of biochemical potency and activity in functional cell-based assays. We used structure-based drug design to introduce key selectivity elements while simultaneously addressing pharmacokinetic liabilities. These efforts culminated in a molecule demonstrating subnanomolar biochemical inhibition of HPK1 and strong in vitro augmentation of TCR signaling in primary human T-cells. Further profiling of this molecule revealed excellent kinase selectivity (347/356 kinases <50% inhibition @ 0.1 μM), a favorable in vitro safety profile, and good projected human pharmacokinetics.

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