31wc | pdb_000031wc
Crystal structure of the HPK1 kinase domain in complex with inhibitor 12
Structural highlights
FunctionM4K1_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.[1] [2] Publication Abstract from PubMedGenerative 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[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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