31wc

Crystal structure of the HPK1 kinase domain in complex with inhibitor 12

spinqualitylabelsall models 31wc, resolution 1.39Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 31wc 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 1.386Å Ligands: A1KCR, 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 Generative artificial intelligence (AI) is now widely applied in medicinal chemistry, with detailed case studies emerging in the literature. Here, we describe an early application of REINVENT, AstraZeneca's in-house generative molecular design platform, to identify new inhibitor scaffolds for hematopoietic progenitor kinase 1 (HPK1). REINVENT was deployed at two stages of the project to address distinct design objectives. For hit identification, transfer learning on kinase-active compounds, followed by reinforcement learning guided by QSAR-based scoring, led to the discovery of three active chemotypes. Subsequently, REINVENT was applied to scaffold hopping, using 3D pharmacophore and docking models as scoring functions, which enabled the identification of two additional active chemotypes. Optimization of one of these scaffolds delivered a compound with potent cellular activity, kinase selectivity, and favorable rat pharmacokinetics. These results demonstrate the value of integrating generative AI with medicinal chemistry expertise and support broader application of the approach in future discovery programs. Generative AI-Assisted Discovery of HPK1 Inhibitors.,Giblin KA, Song K, Chen H, Chen W, Dong Z, Escobar RA, Grebe TP, Grimster NP, Hird AW, Hughes SJ, Kettle JG, Li C, Ma H, Pflug A, Richter M, Schimpl M, Tang H, Wang P, Wrigley G, Wu Y, Yu H, Ziegler RE, Shields JD J Med Chem. 2026 Jul 21. doi: 10.1021/acs.jmedchem.6c01048. PMID:42479954 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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