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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