2. Academic Validation
  3. Discovery of Novel TYRO3/MERTK Dual Inhibitors

Discovery of Novel TYRO3/MERTK Dual Inhibitors

  • J Med Chem. 2025 Apr 24;68(8):8455-8470. doi: 10.1021/acs.jmedchem.5c00009.
Deyu Kong 1,  Jichen Zhao 1,  Daowei Huang 1,  Michael A Stashko 1,  Dan Yan 2,  Ransheng Ding 1,  Shiva K R Guduru 1,  Yubai Zhou 1,  Catherine E Kania 2,  H Shelton Earp 3rd 3 4,  Stephen V Frye 1 4,  Justus M Huelse 2,  Dmitri Kireev 1,  Deborah DeRyckere 2,  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, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, 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: 40215328 DOI: 10.1021/acs.jmedchem.5c00009
Abstract

The TAM (Tyro3, Axl, MERTK) family of Receptor Tyrosine Kinases has roles in oncogenesis and innate immunity, but the relative importance of the family members can differ in different contexts and between tumor types or individual tumors. Dual Tyro3 and MERTK inhibition may be advantageous for treatment of diseases or in tumors that are dependent on their coordinated action. Here, we report the discovery of the first potent dual Tyro3/MERTK inhibitor, UNC9435 (44). UNC9435 has 46-fold and 120-fold selectivity of MERTK over Axl and FLT3, respectively, and selectively against a panel of 30 Other kinases. Tyro3 and MERTK inhibitory activities were confirmed by NanoBRET assays in HEK293 cells, with <0.51 nM EC50 values for both Enzymes and >3000-fold selectivity over Axl. UNC9435 also inhibited Tyro3, MERTK, and downstream oncogenic signaling in Cancer cells and reduced colony formation in non-small cell lung Cancer cultures, indicating its potential as a novel Cancer therapeutic.

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