9h8f

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

spinqualitylabelsall models 9h8f, resolution 1.39Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9h8f is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.393Å Ligands: A1ITB, EDO Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function M4K1_HUMAN Serine/threonine-protein kinase, which may play a role in the response to environmental stress. Appears to act upstream of the JUN N-terminal pathway. May play a role in hematopoietic lineage decisions and growth regulation. Able to autophosphorylate. 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

Proteopedia Page Contributors and Editors (what is this?)

OCA