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.
Jason D Shields  1 David Baker  2 Amber Y S Balazs  1 Gayathri Bommakanti  1 Robert Casella  3 Shenggen Cao  4 Steve Cook  3 Randolph A Escobar  1 Stephen Fawell  1 Francis D Gibbons  1 Kathryn A Giblin  5 Frederick W Goldberg  5 Eric Gosselin  1 Tyler Grebe  1 Niresh Hariparsad  1 Holia Hatoum-Mokdad  1 Rachel Howells  5 Samantha J Hughes  5 Anne Jackson  2 Iswarya Karapa Reddy  1 Jason G Kettle  5 Gillian M Lamont  5 Scott Lamont  5 Min Li  4 Sten O Nilsson Lill  6 Deanna A Mele  1 Anthony J Metrano  1 Adelphe M Mfuh  1 Lucas A Morrill  1 Bo Peng  1 Alexander Pflug  2 Theresa A Proia  1 Hadi Rezaei  1 Ryan Richards  1 Magdalena Richter  2 Kevin J Robbins  1 Maryann San Martin  1 Marianne Schimpl  2 Alwin G Schuller  1 Li Sha  1 Minhui Shen  1 James E Sheppeck 2nd  1 Meha Singh  7 Stephen Stokes  5 Kun Song  1 Yuanyuan Sun  4 Haoran Tang  2 David J Wagner  1 Jianyan Wang  3 Yanjun Wang  1 David M Wilson  5 Allan Wu  7 Chengyan Wu  4 Dedong Wu  3 Ye Wu  1 Kevin Xu  1 Yue Yang  4 Tieguang Yao  4 Minwei Ye  1 Andrew X Zhang  7 Hui Zhang  4 Xiang Zhai  7 Yanxiao Zhou  4 Robert E Ziegler  1 Neil P Grimster  1
Affiliations
  • 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.
Abstract

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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