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

Seung Hyun Bae, Jung Hoon Kim, Tae Hyun Park, Kyeong Lee, Byung Il Lee, Hyonchol Jang

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)1450-1460
Number of pages11
JournalExperimental and Molecular Medicine
Volume54
Issue number9
DOIs
StatePublished - Sep 2022

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