9kry
Crystal structure Of MerTK kinase domain in complex With compound 1
Structural highlights
DiseaseMERTK_HUMAN Defects in MERTK are the cause of retinitis pigmentosa type 38 (RP38) [MIM:613862. RP38 is a retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well.[1] FunctionMERTK_HUMAN Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding to several ligands including LGALS3, TUB, TULP1 or GAS6. Regulates many physiological processes including cell survival, migration, differentiation, and phagocytosis of apoptotic cells (efferocytosis). Ligand binding at the cell surface induces autophosphorylation of MERTK on its intracellular domain that provides docking sites for downstream signaling molecules. Following activation by ligand, interacts with GRB2 or PLCG2 and induces phosphorylation of MAPK1, MAPK2, FAK/PTK2 or RAC1. MERTK signaling plays a role in various processes such as macrophage clearance of apoptotic cells, platelet aggregation, cytoskeleton reorganization and engulfment. Functions in the retinal pigment epithelium (RPE) as a regulator of rod outer segments fragments phagocytosis. Plays also an important role in inhibition of Toll-like receptors (TLRs)-mediated innate immune response by activating STAT1, which selectively induces production of suppressors of cytokine signaling SOCS1 and SOCS3.[2] Publication Abstract from PubMedTumor-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 alphaC helix. By integrating structural biology, medicinal chemistry, protein stabilization assays, and molecular docking studies, we identified compound 11, which demonstrates potent inhibition and selectivity for MerTK. Pharmacokinetic evaluations and in vivo studies further reveal compound 11 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 alphaC helix conformation. Structure-Based Design of Potent and Selective MerTK Inhibitors by Modulating the Conformation of alphaC Helix.,Peng YH, Li MC, Yen WC, Yeh TK, Hsueh CC, Kuo FM, Lai YL, Chang L, Lee LC, Chen PY, Yen KJ, Chang TY, Sun HY, Chang CY, Hsieh SH, Yang CM, Hsieh HP, Wu SY J Med Chem. 2025 Jun 12;68(11):10877-10896. doi: 10.1021/acs.jmedchem.4c03092. , Epub 2025 May 20. PMID:40391976[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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