Discovery of GNE-6893, a Potent, Selective, Orally Bioavailable Small Molecule Inhibitor of HPK1
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 <i>in vitro</i> 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 <i>in vitro</i> safety profile, and good projected human pharmacokinetics.
Authors
- Dian Su (ORCID: https://orcid.org/0000-0003-4572-462X)
- Michael Siu (ORCID: https://orcid.org/0000-0002-2822-6584)
- Rohan Mendonca
- Timothy P. Heffron
- Michael Lainchbury
- Edna F. Choo (ORCID: https://orcid.org/0000-0003-4200-8302)
- Baihua Hu (ORCID: https://orcid.org/0000-0002-1340-5811)
- Bryan Chan (ORCID: https://orcid.org/0000-0002-1086-4596)
- Ping Wu (ORCID: https://orcid.org/0000-0002-1018-2907)
- Weiru Wang (ORCID: https://orcid.org/0000-0001-8845-301X)
- James R. Kiefer (ORCID: https://orcid.org/0000-0001-6317-0902)
- John C. Tellis (ORCID: https://orcid.org/0000-0003-1675-9639)
- Satoko Kakiuchi-Kiyota (ORCID: https://orcid.org/0000-0002-4028-8817)
- Xiangnan Du
- Eileen M. Seward
- BinQing Wei (ORCID: https://orcid.org/0000-0002-3654-3459)
- Chris Sneeringer
- Jodie Pang (ORCID: https://orcid.org/0000-0003-2984-2781)
- Vijay A. Sethuraman (ORCID: https://orcid.org/0000-0003-4624-1355)
- Sushant Malhotra
- Lewis Gazzard (ORCID: https://orcid.org/0000-0003-4448-2462)
- Le An
- Yong Chen (ORCID: https://orcid.org/0000-0002-7029-6201)
- Xifeng Luo
- John G. Moffat
- Grace K.Y. Chan
- Jonathan L. Linehan
- Yinqing Ran
Institutions
- Charles River Laboratories (United Kingdom) (GB)
Publication Details
- Journal
- ACS Medicinal Chemistry Letters
- Published
- 2024-09-03
- DOI
- https://doi.org/10.1021/acsmedchemlett.4c00319
- Citations
- 13
- Primary Topic
- Protein Tyrosine Phosphatases
- Type
- article
- Field-Weighted Citation Impact
- 3.04
Funders
- Johns Hopkins University
- Curtin University of Technology
- Pharmaron
- Genentech