Discovery and Optimization of Pyrazine Carboxamide AZ3246, a Selective HPK1 Inhibitor
Jason D. Shields, David Baker, Amber Balazs, Gayathri Bommakanti, Robert Casella, Shenggen Cao, Steve Cook, Randolph Escobar, Stephen E. Fawell, Francis D. Gibbons, Kathryn A. Giblin, Frederick W. Goldberg, Éric Gosselin, Tyler Grebe, Niresh Hariparsad, Holia Hatoum‐Mokdad, Rachel Howells, Samantha Jane Hughes, Anne Jackson, Iswarya Karapa Reddy, Jason G. Kettle, Gillian M. Lamont, Scott G. Lamont, Min Li, Sten O. Nilsson Lill, Deanna A. Mele, Anthony J. Metrano, Adelphe M. Mfuh, Lucas A. Morrill, Bo Peng, A. Pflug, Theresa A. Proia, Hadi Rezaei, Ryan M. Richards, Magdalena Richter, Kevin J. Robbins, Maryann San Martin, Marianne Schimpl, Alwin G. Schuller, Sha Li, Minhui Shen, James E. Sheppeck, Meha Singh, S.P. Stokes, Kun Song, Yuanyuan Sun, Haoran Tang, David J. Wagner, Jianyan Wang, Yanjun Wang, David M. Wilson, Allan Wu, Chenyan Wu, Dedong Wu, Ye Wu, Kevin Y. Xu, Yue Yang, Tieguang Yao, Minwei Ye, Andrew X. Zhang, Hui Zhang, Xiang Zhai, Yanxiao Zhou, Robert Ziegler, Neil P. Grimster
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 EC 50 of 90 nM without inhibiting antagonistic kinases, exhibits pharmacokinetic properties consistent with oral dosing, and demonstrates antitumor activity in the EMT6 syngeneic mouse model.