9KRZ
Crystal structure Of MerTK kinase domain in complex with compound 11
This is a non-PDB format compatible entry.
Summary for 9KRZ
| Entry DOI | 10.2210/pdb9krz/pdb |
| Descriptor | Tyrosine-protein kinase Mer, ~{N}-[4-[5-[3-[(dimethylamino)methyl]phenyl]-6-(1-methylpyrazol-4-yl)furo[2,3-d]pyrimidin-4-yl]oxyphenyl]-2-(4-fluorophenyl)-1-methyl-3-oxidanylidene-pyrazole-4-carboxamide (3 entities in total) |
| Functional Keywords | kinase, dynamic dimer, complex, tam, immune regulation, allosteric binding inhibitor, type 2 inhibitor, transferase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 69029.82 |
| Authors | |
| Primary citation | Peng, Y.H.,Li, M.C.,Yen, W.C.,Yeh, T.K.,Hsueh, C.C.,Kuo, F.M.,Lai, Y.L.,Chang, L.,Lee, L.C.,Chen, P.Y.,Yen, K.J.,Chang, T.Y.,Sun, H.Y.,Chang, C.Y.,Hsieh, S.H.,Yang, C.M.,Hsieh, H.P.,Wu, S.Y. Structure-Based Design of Potent and Selective MerTK Inhibitors by Modulating the Conformation of alpha C Helix. J.Med.Chem., 68:10877-10896, 2025 Cited by PubMed Abstract: Tumor-associated macrophages play an important role in cancer progression and immunosuppression, making their receptors promising therapeutic targets. MerTK, a TAM receptor, regulates macrophage efferocytosis and polarization, and its inhibition holds potential for tumor growth suppression and immune modulation. However, Tyro3, another TAM receptor, is involved in neurogenesis, highlighting the need to selectively target MerTK while avoiding Tyro3 inhibition to prevent neurotoxicity. In this study, we present a novel strategy for designing MerTK-selective inhibitors by modulating the conformational dynamics of its αC helix. By integrating structural biology, medicinal chemistry, protein stabilization assays, and molecular docking studies, we identified compound , which demonstrates potent inhibition and selectivity for MerTK. Pharmacokinetic evaluations and studies further reveal compound as a promising candidate for further development. Our findings not only advance the understanding of the MerTK-specific mechanism but also propose a strategy for designing selective kinase inhibitors targeting the αC helix conformation. PubMed: 40391976DOI: 10.1021/acs.jmedchem.4c03092 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.6 Å) |
Structure validation
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