2. Academic Validation
  3. UNC5293, a potent, orally available and highly MERTK-selective inhibitor

UNC5293, a potent, orally available and highly MERTK-selective inhibitor

  • Eur J Med Chem. 2021 Aug 5;220:113534. doi: 10.1016/j.ejmech.2021.113534.
Hongchao Zheng 1,  Jichen Zhao 1,  Bing Li 1,  Weihe Zhang 1,  Michael A Stashko 1,  Katherine A Minson 2,  Madeline G Huey 2,  Yubai Zhou 1,  Henry Shelton Earp 3,  Dmitri Kireev 1,  Douglas K Graham 2,  Deborah DeRyckere 2,  Stephen V Frye 4,  Xiaodong Wang 5
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, NC, 27599, USA.
  • 2 Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta and Department of Pediatrics, School of Medicine, Emory University, Atlanta, GA, 30322, USA.
  • 3 Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA; Lineberger Comprehensive Cancer Center, Department of Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
  • 4 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, NC, 27599, USA; Lineberger Comprehensive Cancer Center, Department of Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
  • 5 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, NC, 27599, USA; Lineberger Comprehensive Cancer Center, Department of Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA. Electronic address: [email protected].
PMID: 34038857 DOI: 10.1016/j.ejmech.2021.113534
Abstract

Inhibition of MER receptor tyrosine kinase (MERTK) causes direct tumor cell killing and stimulation of the innate immune response. Therefore, MERTK has been identified as a therapeutic target in a wide variety of human tumors. Clinical trials targeting MERTK have recently been initiated, however, none of these drugs are MERTK-specific. Herein, we present the discovery of a highly MERTK-selective inhibitor UNC5293 (24). UNC5293 has subnanomolar activity against MERTK with an excellent Ambit selectivity score (S50 (100 nM) = 0.041). It mediated potent and selective inhibition of MERTK in cell-based assays. Furthermore, it has excellent mouse PK properties (7.8 h half-life and 58% oral bioavailability) and was active in bone marrow leukemia cells in a murine model.

Keywords

Alkyl pyrrolopyrimidine; Cancer immunotherapy; MERTK; MERTK-Specific inhibitor; Magic methyl; TAM kinase.

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