BMS794833 inhibits macrophage efferocytosis by directly binding to MERTK and inhibiting its activity

Myeloid epithelial reproductive proto-oncogene tyrosine kinase (MERTK) plays an essential role in modulating cancer immune tolerance by regulating macrophage efferocytosis. Studies are underway to develop small-molecule chemicals that inhibit MERTK as cancer immunotherapeutic agents, but these efforts are in their early stages. This study identified BMS794833, whose primary targets are MET and VEGFR2, as a potent MERTK inhibitor and developed a real-time efferocytosis monitoring system. The X-ray cocrystal structure revealed that BMS794833 was in contact with the ATP-binding pocket and the allosteric back pocket, rendering MERTK inactive. Homogeneous time-resolved fluorescence kinetic and Western blotting analyses showed that BMS794833 competitively inhibited MERTK activity in vitro and inhibited the autophosphorylation of MERTK in macrophages. We developed a system to monitor MERTK-dependent efferocytosis in real time, and using this system, we confirmed that BMS794833 significantly inhibited the efferocytosis of differentiated macrophages. Finally, BMS794833 significantly inhibited efferocytosis in vivo in a mouse model. These data show that BMS794833 is a type II MERTK inhibitor that regulates macrophage efferocytosis. In addition, the real-time efferocytosis monitoring technology developed in this study has great potential for future applications. Cancer: drug could block evading the immune system An enzyme that is over-expressed in cancers and helps promote immune evasion could be inhibited by a small-molecule anticancer drug currently in phase 1 clinical trials. White blood cells called macrophages rapidly clear dead cells to avoid inappropriate inflammatory responses in a process known as efferocytosis. The MERTK enzyme receptor, expressed by macrophages, plays a key role. However, MERTK is over-expressed in many cancers, leading to aberrant efferocytosis and immune evasion. Using mouse models, Hyonchol Jang and Byung Il Lee at the National Cancer Center, Goyang, South Korea, and co-workers demonstrated that the drug BMS794833 is an effective inhibitor of MERTK-dependent efferocytosis. Using X-ray crystallography, they determined that the drug binds to and inactivates MERTK. To potentially identify other MERTK inhibitors, they also developed a novel assay that monitors efferocytosis in real time.