31WC
Crystal structure of the HPK1 kinase domain in complex with inhibitor 12
This is a non-PDB format compatible entry.
Summary for 31WC
| Entry DOI | 10.2210/pdb31wc/pdb |
| Descriptor | Mitogen-activated protein kinase kinase kinase kinase 1, 2-cyclopropyl-8-(3-methoxy-1-methyl-pyrazol-4-yl)-3-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrido[3,4-b]pyrazin-5-amine, 1,2-ETHANEDIOL, ... (4 entities in total) |
| Functional Keywords | hpk1 kinase domain, inhibitor, drug discovery, transferase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 33437.75 |
| Authors | |
| Primary citation | Giblin, K.A.,Song, K.,Chen, H.,Chen, W.,Dong, Z.,Escobar, R.A.,Grebe, T.P.,Grimster, N.P.,Hird, A.W.,Hughes, S.J.,Kettle, J.G.,Li, C.,Ma, H.,Pflug, A.,Richter, M.,Schimpl, M.,Tang, H.,Wang, P.,Wrigley, G.,Wu, Y.,Yu, H.,Ziegler, R.E.,Shields, J.D. Generative AI-Assisted Discovery of HPK1 Inhibitors. J.Med.Chem., 2026 Cited by PubMed Abstract: 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. PubMed: 42479954DOI: 10.1021/acs.jmedchem.6c01048 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.386 Å) |
Structure validation
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