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

Hongchao Zheng; Jichen Zhao; Bing Li; Weihe Zhang; Michael A Stashko; Katherine A Minson; Madeline G Huey; Yubai Zhou; Henry Shelton Earp; Dmitri Kireev; Douglas K Graham; Deborah DeRyckere; Stephen V Frye; Xiaodong Wang

doi:10.1016/j.ejmech.2021.113534

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. Epub 2021 May 17.

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: xiaodonw@unc.edu.

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.

MeSH terms

Administration, Oral
Animals
Cells, Cultured
Dose-Response Relationship, Drug
Humans
Mice
Mice, Congenic
Mice, Inbred NOD
Molecular Structure
Protein Kinase Inhibitors / administration & dosage
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Structure-Activity Relationship
c-Mer Tyrosine Kinase / antagonists & inhibitors*
c-Mer Tyrosine Kinase / metabolism

Substances

Protein Kinase Inhibitors
MERTK protein, human
c-Mer Tyrosine Kinase