Discovery and Optimization of Pyrazine Carboxamide AZ3246, a Selective HPK1 Inhibitor
- J Med Chem. 2025 Feb 27;68(4):4582-4595. doi: 10.1021/acs.jmedchem.4c02631.
- 1. Early Oncology R&D, AstraZeneca, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
- 2. Discovery Sciences, R&D, AstraZeneca, 1 Francis Crick Avenue, Cambridge CB2 0AA, U.K.
- 3. Advanced Drug Delivery, Pharmaceutical Sciences, R&D, AstraZeneca, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
- 4. Pharmaron Beijing Co., Ltd., 6 Taihe Road BDA, Beijing 100176, P. R. China.
- 5. Early Oncology R&D, AstraZeneca, 1 Francis Crick Avenue, Cambridge CB2 0AA, U.K.
- 6. Pharmaceutical Sciences, R&D, AstraZeneca, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
- 7. Discovery Sciences, R&D, AstraZeneca, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of the T cell receptor signaling pathway and is therefore a target of interest for immunooncology. Nonselective HPK1 inhibitors may affect Other kinase components of T cell activation, blunting the beneficial impact of enhanced T cell activity that results from HPK1 inhibition itself. Here, we report the discovery of pyrazine carboxamide HPK1 inhibitors and their optimization through structure-based drug design to afford a highly selective HPK1 inhibitor, compound 24 (AZ3246). This compound induces IL-2 secretion in T cells with an EC50 of 90 nM without inhibiting antagonistic kinases, exhibits pharmacokinetic properties consistent with oral dosing, and demonstrates antitumor activity in the EMT6 syngeneic mouse model.
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Cat. No.Product NameDescriptionTargetResearch Area
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Research Areas: Cancer