Discovery and Optimization of Pyrazine Carboxamide AZ3246, a Selective HPK1 Inhibitor
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 <b>24</b> (AZ3246). This compound induces IL-2 secretion in T cells with an EC<sub>50</sub> of 90 nM without inhibiting antagonistic kinases, exhibits pharmacokinetic properties consistent with oral dosing, and demonstrates antitumor activity in the EMT6 syngeneic mouse model.
Authors
- Haoran Tang (ORCID: https://orcid.org/0000-0002-0963-7230)
- Deanna A. Mele (ORCID: https://orcid.org/0000-0002-6429-4269)
- Minhui Shen
- Andrew X. Zhang (ORCID: https://orcid.org/0000-0003-0406-2404)
- Randolph Escobar (ORCID: https://orcid.org/0000-0001-7476-7747)
- Alwin G. Schuller (ORCID: https://orcid.org/0000-0001-9163-5885)
- Xiang Zhai (ORCID: https://orcid.org/0000-0003-0639-8710)
- Theresa A. Proia
- Adelphe M. Mfuh (ORCID: https://orcid.org/0000-0002-8619-1455)
- David J. Wagner (ORCID: https://orcid.org/0000-0002-5805-930X)
- Tyler Grebe
- Jason D. Shields (ORCID: https://orcid.org/0000-0002-9015-8594)
- David Baker (ORCID: https://orcid.org/0000-0002-8872-8711)
- S.P. Stokes
- Yanmin Zhou (ORCID: https://orcid.org/0000-0002-4173-6765)
- Marianne Schimpl (ORCID: https://orcid.org/0000-0003-2284-5250)
- A. Pflug (ORCID: https://orcid.org/0000-0002-4680-1298)
- Anne Jackson
- David M. Wilson (ORCID: https://orcid.org/0000-0002-1095-046X)
- Shenggen Cao
- Minwei Ye
- Jason G. Kettle (ORCID: https://orcid.org/0000-0001-7373-0758)
- Robert Ziegler (ORCID: https://orcid.org/0000-0001-9574-8780)
- Amber Balazs (ORCID: https://orcid.org/0000-0002-5556-6795)
- Holia Hatoum‐Mokdad
- Min Li (ORCID: https://orcid.org/0000-0003-2796-294X)
- Maryann San Martin (ORCID: https://orcid.org/0009-0006-9371-410X)
- Magdalena Richter (ORCID: https://orcid.org/0000-0003-1818-5288)
- Robert Casella
- Chenyan Wu (ORCID: https://orcid.org/0000-0002-6855-4486)
- Tieguang Yao
- Neil P. Grimster (ORCID: https://orcid.org/0000-0003-0088-1250)
- Niresh Hariparsad (ORCID: https://orcid.org/0000-0002-6290-5329)
- Kevin Y. Xu (ORCID: https://orcid.org/0000-0001-6595-695X)
- Gayathri Bommakanti (ORCID: https://orcid.org/0000-0002-3420-2802)
- Lucas A. Morrill
- Dedong Wu (ORCID: https://orcid.org/0000-0002-9152-5093)
- Ye Wu (ORCID: https://orcid.org/0000-0003-4974-0774)
- Francis D. Gibbons (ORCID: https://orcid.org/0000-0003-1606-1740)
- Sten O. Nilsson Lill (ORCID: https://orcid.org/0000-0003-4818-8084)
- Samantha Jane Hughes (ORCID: https://orcid.org/0000-0001-6340-2646)
- James E. Sheppeck
- Bo Peng (ORCID: https://orcid.org/0000-0003-4482-2885)
- Anthony J. Metrano (ORCID: https://orcid.org/0000-0002-2599-8917)
- Ryan M. Richards (ORCID: https://orcid.org/0000-0001-8792-3964)
- Éric Gosselin
- Kevin J. Robbins
- Meha Singh
- Kathryn A. Giblin (ORCID: https://orcid.org/0000-0003-2446-6326)
- Frederick W. Goldberg (ORCID: https://orcid.org/0000-0002-4874-1700)
- Rachel Howells (ORCID: https://orcid.org/0009-0000-5850-7339)
- Jianyan Wang (ORCID: https://orcid.org/0000-0001-7831-7030)
- Stephen E. Fawell (ORCID: https://orcid.org/0000-0002-1962-891X)
- Iswarya Karapa Reddy
- Hui Zhang (ORCID: https://orcid.org/0000-0002-0756-9334)
- Yue Yang (ORCID: https://orcid.org/0000-0001-5876-6576)
- Sha Li (ORCID: https://orcid.org/0000-0002-6520-6806)
- Yuanyuan Sun
- Yanjun Wang (ORCID: https://orcid.org/0000-0001-5513-0177)
- Kun Song (ORCID: https://orcid.org/0000-0001-9409-1991)
- Steve Cook
- Hadi Rezaei
- Allan Wu
- Scott G. Lamont
- Gillian M. Lamont
Institutions
- AstraZeneca (Netherlands) (NL)
- AstraZeneca (Sweden) (SE)
- AstraZeneca (United States) (US)
- AstraZeneca (Germany) (DE)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-02-10
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c02631
- Citations
- 16
- Primary Topic
- Immune Cell Function and Interaction
- Type
- article
- Field-Weighted Citation Impact
- 12.76