Discovery of Novel Macrocyclic MERTK/AXL Dual Inhibitors.

Autor:	Kong D; Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, Chapel Hill, North Carolina 27599-7355, United States., Tian Q; Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, Chapel Hill, North Carolina 27599-7355, United States., Chen Z; Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, Chapel Hill, North Carolina 27599-7355, United States., Zheng H; Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, Chapel Hill, North Carolina 27599-7355, United States., Stashko MA; Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, Chapel Hill, North Carolina 27599-7355, United States., Yan D; Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta and Department of Pediatrics, School of Medicine, Emory University, Atlanta, Georgia 30322, United States., Earp HS; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.; Lineberger Comprehensive Cancer Center, Department of Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States., Frye SV; Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, Chapel Hill, North Carolina 27599-7355, United States.; Lineberger Comprehensive Cancer Center, Department of Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States., DeRyckere D; Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta and Department of Pediatrics, School of Medicine, Emory University, Atlanta, Georgia 30322, United States., Kireev D; Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, Chapel Hill, North Carolina 27599-7355, United States., Graham DK; Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta and Department of Pediatrics, School of Medicine, Emory University, Atlanta, Georgia 30322, United States., Wang X; Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, Chapel Hill, North Carolina 27599-7355, United States.; Lineberger Comprehensive Cancer Center, Department of Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2024 Apr 11; Vol. 67 (7), pp. 5866-5882. Date of Electronic Publication: 2024 Mar 31.
DOI:	10.1021/acs.jmedchem.4c00148
Abstrakt:	MERTK and AXL are members of the TAM (TYRO3, AXL, MERTK) family of receptor tyrosine kinases that are aberrantly expressed and have been implicated as therapeutic targets in a wide variety of human tumors. Dual MERTK and AXL inhibition could provide antitumor action mediated by both direct tumor cell killing and modulation of the innate immune response in some tumors such as nonsmall cell lung cancer. We utilized our knowledge of MERTK inhibitors and a structure-based drug design approach to discover a novel class of macrocyclic dual MERTK/AXL inhibitors. The lead compound 43 had low-nanomolar activity against both MERTK and AXL and good selectivity over TYRO3 and FLT3. Its target engagement and selectivity were also confirmed by NanoBRET and cell-based MERTK and AXL phosphorylation assays. Compound 43 had excellent pharmacokinetic properties (large AUC and long half-life) and mediated antitumor activity against lung cancer cell lines, indicating its potential as a therapeutic agent.
Databáze:	MEDLINE
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