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Publication Abstract from PubMed

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.

Discovery and Optimization of Pyrazine Carboxamide AZ3246, a Selective HPK1 Inhibitor.,Shields JD, Baker D, Balazs AYS, Bommakanti G, Casella R, Cao S, Cook S, Escobar RA, Fawell S, Gibbons FD, Giblin KA, Goldberg FW, Gosselin E, Grebe T, Hariparsad N, Hatoum-Mokdad H, Howells R, Hughes SJ, Jackson A, Karapa Reddy I, Kettle JG, Lamont GM, Lamont S, Li M, Lill SON, Mele DA, Metrano AJ, Mfuh AM, Morrill LA, Peng B, Pflug A, Proia TA, Rezaei H, Richards R, Richter M, Robbins KJ, San Martin M, Schimpl M, Schuller AG, Sha L, Shen M, Sheppeck JE 2nd, Singh M, Stokes S, Song K, Sun Y, Tang H, Wagner DJ, Wang J, Wang Y, Wilson DM, Wu A, Wu C, Wu D, Wu Y, Xu K, Yang Y, Yao T, Ye M, Zhang AX, Zhang H, Zhai X, Zhou Y, Ziegler RE, Grimster NP J Med Chem. 2025 Feb 10. doi: 10.1021/acs.jmedchem.4c02631. PMID:39928839^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.