MerTK Induces Dysfunctional Dendritic Cells by Metabolic Reprogramming.

Checkpoint inhibitors, specifically anti-programmed cell death protein 1 (PD1), have shown success in treating metastatic melanoma; however, some patients develop resistance. Dendritic cells (DC) play a key role in initiating an immune response, but in certain circumstances they become ineffective. We investigated the role of MerTK, a receptor tyrosine kinase responsible for myeloid cell clearance of dead cells, in the regulation of DC function and metabolism in the tumor microenvironment.

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.

Highly Selective MERTK Inhibitors Achieved by a Single Methyl Group.

Although all kinases share the same ATP binding pocket, subtle differences in the residues that form the pocket differentiate individual kinases' affinity for ATP competitive inhibitors. We have found that by introducing a single methyl group, the selectivity of our MERTK inhibitors over another target, FLT3, was increased up to 1000-fold (compound 31). Compound 19 was identified as an in vivo tool compound with subnanomolar activity against MERTK and 38-fold selectivity over FLT3 in vitro.