2. Academic Validation
  3. Discovery of Novel Macrocyclic MERTK/AXL Dual Inhibitors

Discovery of Novel Macrocyclic MERTK/AXL Dual Inhibitors

  • J Med Chem. 2024 Apr 11;67(7):5866-5882. doi: 10.1021/acs.jmedchem.4c00148.
Deyu Kong 1,  Qiang Tian 1,  Zhilong Chen 1,  Hongchao Zheng 1,  Michael A Stashko 1,  Dan Yan 2,  H Shelton Earp 3 4,  Stephen V Frye 1 4,  Deborah DeRyckere 2,  Dmitri Kireev 1,  Douglas K Graham 2,  Xiaodong Wang 1 4
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
  • 4 Lineberger Comprehensive Cancer Center, Department of Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
PMID: 38556760 DOI: 10.1021/acs.jmedchem.4c00148
Abstract

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.

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