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

• Published in: European journal of medicinal chemistry 2021-08, Vol.220, p.113534-113534, Article 113534
• Main Authors: Zheng, Hongchao, Zhao, Jichen, Li, Bing, Zhang, Weihe, Stashko, Michael A., Minson, Katherine A., Huey, Madeline G., Zhou, Yubai, Earp, Henry Shelton, Kireev, Dmitri, Graham, Douglas K., DeRyckere, Deborah, Frye, Stephen V., Wang, Xiaodong
• Format: Article
• Language: English
• Subjects: Alkyl pyrrolopyrimidine; Cancer immunotherapy; Magic methyl; MERTK; MERTK-Specific inhibitor; TAM kinase
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2021.113534

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. [Display omitted] •Inhibition of MERTK is known to mediate both direct tumor cell killing and activation of the innate anti-tumor immunity.•UNC5293 (24) is a MERTK-selective and potent inhibitor (Ki for MERTK is 190 pM).•UNC5293 mediated potent and selective inhibition of MERTK in cell-based assays.•UNC5293 has excellent mouse PK properties and was active in bone marrow leukemia cells in a murine model.