9H8F

Crystal structure of HPK1 T165E/S171E in complex with pyrazine carboxamide inhibitor AZ3246 (compound 24)

This is a non-PDB format compatible entry.

Summary for 9H8F

• Entry DOI: 10.2210/pdb9h8f/pdb
• Descriptor: Mitogen-activated protein kinase kinase kinase kinase 1, 5-cyclopropyl-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[[3-methyl-1-[2,2,2-tris(fluoranyl)ethyl]pyrazol-4-yl]amino]pyrazine-2-carboxamide, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: transferase, kinase, type 1 inhibitor, structure-based drug design
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 33543.80

Authors

Schimpl, M.,Pflug, A. (deposition date: 2024-10-29, release date: 2025-02-19, Last modification date: 2025-03-05)

Primary citation

Shields, J.D.,Baker, D.,Balazs, A.Y.S.,Bommakanti, G.,Casella, R.,Cao, S.,Cook, S.,Escobar, R.A.,Fawell, S.,Gibbons, F.D.,Giblin, K.A.,Goldberg, F.W.,Gosselin, E.,Grebe, T.,Hariparsad, N.,Hatoum-Mokdad, H.,Howells, R.,Hughes, S.J.,Jackson, A.,Karapa Reddy, I.,Kettle, J.G.,Lamont, G.M.,Lamont, S.,Li, M.,Lill, S.O.N.,Mele, D.A.,Metrano, A.J.,Mfuh, A.M.,Morrill, L.A.,Peng, B.,Pflug, A.,Proia, T.A.,Rezaei, H.,Richards, R.,Richter, M.,Robbins, K.J.,San Martin, M.,Schimpl, M.,Schuller, A.G.,Sha, L.,Shen, M.,Sheppeck 2nd, J.E.,Singh, M.,Stokes, S.,Song, K.,Sun, Y.,Tang, H.,Wagner, D.J.,Wang, J.,Wang, Y.,Wilson, D.M.,Wu, A.,Wu, C.,Wu, D.,Wu, Y.,Xu, K.,Yang, Y.,Yao, T.,Ye, M.,Zhang, A.X.,Zhang, H.,Zhai, X.,Zhou, Y.,Ziegler, R.E.,Grimster, N.P.
Discovery and Optimization of Pyrazine Carboxamide AZ3246, a Selective HPK1 Inhibitor.
J.Med.Chem., 68:4582-4595, 2025

PubMed 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 (AZ3246). This compound induces IL-2 secretion in T cells with an EC of 90 nM without inhibiting antagonistic kinases, exhibits pharmacokinetic properties consistent with oral dosing, and demonstrates antitumor activity in the EMT6 syngeneic mouse model.

PubMed: 39928839
DOI: 10.1021/acs.jmedchem.4c02631

Experimental method

X-RAY DIFFRACTION (1.393 Å)