1. Academic Validation
  2. Discovery and Optimization of Pyrazine Carboxamide AZ3246, a Selective HPK1 Inhibitor

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

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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