2. Academic Validation
  3. UNC9426, a Potent and Orally Bioavailable TYRO3-Specific Inhibitor

UNC9426, a Potent and Orally Bioavailable TYRO3-Specific Inhibitor

  • J Med Chem. 2025 Mar 27;68(6):6665-6682. doi: 10.1021/acs.jmedchem.5c00048.
Deyu Kong 1,  Xiangbo Yang 1,  Samantha Judd 2,  Dan Yan 3,  Stephanie Springborn 2,  Michael A Stashko 1,  Adam Kidwell 2,  Justus M Huelse 3,  Dmitri Kireev 1,  Douglas K Graham 3,  Deborah DeRyckere 3,  Brian Branchford 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 Versiti Blood Research Institute, Wauwatosa, Wisconsin 53226, United States.
  • 3 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.
  • 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: 40070132 DOI: 10.1021/acs.jmedchem.5c00048
Abstract

Tyro3 plays a critical role in platelet aggregation as a platelet response amplifier. Selective inhibition of Tyro3 may provide therapeutic benefits for treating thrombosis and related diseases without increasing bleeding risk. We employed a structure-based approach and discovered a novel and potent Tyro3 Inhibitor UNC9426 (12) with an excellent Ambit selectivity score (S50 (1.0 μM) = 0.026) and favorable pharmacokinetic properties in mice. Treatment with UNC9426 reduced platelet aggregation without increasing bleeding time and blocked TYRO3-dependent functions in tumor cells and macrophages, implicating its utility for multiple indications.

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