| Structural highlights
Disease
[MERTK_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]
Function
[MERTK_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 PubMed
Controlling which particular members of a large protein family are targeted by a drug is key to achieving a desired therapeutic response. In this study, we report a rational data-driven strategy for achieving restricted polypharmacology in the design of antitumor agents selectively targeting the TYRO3, AXL, and MERTK (TAM) family tyrosine kinases. Our computational approach, based on the concept of fragments in structural environments (FRASE), distills relevant chemical information from structural and chemogenomic databases to assemble a three-dimensional inhibitor structure directly in the protein pocket. Target engagement by the inhibitors designed led to disruption of oncogenic phenotypes as demonstrated in enzymatic assays and in a panel of cancer cell lines, including acute lymphoblastic and myeloid leukemia (ALL/AML) and nonsmall cell lung cancer (NSCLC). Structural rationale underlying the approach was corroborated by X-ray crystallography. The lead compound demonstrated potent target inhibition in a pharmacodynamic study in leukemic mice.
Data-Driven Construction of Antitumor Agents with Controlled Polypharmacology.,Da C, Zhang D, Stashko M, Vasileiadi E, Parker RE, Minson KA, Huey MG, Huelse JM, Hunter D, Gilbert TSK, Norris-Drouin J, Miley M, Herring LE, Graves LM, DeRyckere D, Earp HS, Graham DK, Frye SV, Wang X, Kireev D J Am Chem Soc. 2019 Oct 2;141(39):15700-15709. doi: 10.1021/jacs.9b08660. Epub, 2019 Sep 20. PMID:31497954[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Gal A, Li Y, Thompson DA, Weir J, Orth U, Jacobson SG, Apfelstedt-Sylla E, Vollrath D. Mutations in MERTK, the human orthologue of the RCS rat retinal dystrophy gene, cause retinitis pigmentosa. Nat Genet. 2000 Nov;26(3):270-1. PMID:11062461 doi:10.1038/81555
- ↑ Shimojima M, Takada A, Ebihara H, Neumann G, Fujioka K, Irimura T, Jones S, Feldmann H, Kawaoka Y. Tyro3 family-mediated cell entry of Ebola and Marburg viruses. J Virol. 2006 Oct;80(20):10109-16. PMID:17005688 doi:80/20/10109
- ↑ Da C, Zhang D, Stashko M, Vasileiadi E, Parker RE, Minson KA, Huey MG, Huelse JM, Hunter D, Gilbert TSK, Norris-Drouin J, Miley M, Herring LE, Graves LM, DeRyckere D, Earp HS, Graham DK, Frye SV, Wang X, Kireev D. Data-Driven Construction of Antitumor Agents with Controlled Polypharmacology. J Am Chem Soc. 2019 Oct 2;141(39):15700-15709. doi: 10.1021/jacs.9b08660. Epub, 2019 Sep 20. PMID:31497954 doi:http://dx.doi.org/10.1021/jacs.9b08660
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