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

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 (S-50 (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. (C) 2021 Elsevier Masson SAS. All rights reserved.

Automated summary

Inhibition of MER receptor tyrosine kinase (MERTK) contributes to tumor cell killing and stimulation of the immune response. UNC5293 is a highly selective MERTK inhibitor with potent and selective inhibition in cell-based assays, excellent mouse PK properties, and activity in leukemia cells in a murine model.