Identification of a highly selective inhibitor for ABHD12 and elucidation of its biological functions enabled by Activity-Based Protein Profiling (ABPP)

Abstract

ABHD12 is a major enzyme that metabolizes lysophosphatidylserine (lyso-PS), a class of immunomodulatory lipids that has been shown to regulate functions of immune cells. Our understanding of the physiological functions of ABHD12 has been limited by a lack of selective and in vivo-active ABHD12 inhibitors. In this study, we set out to investigate the physiological functions of ABHD12 by using selective chemical probes for ABHD12. We have identified a selective and in vivo active ABHD12 inhibitor DO 264 as well as a structurally related inactive control probe (S)-DO 271 after a compound library screening and the lead optimization. DO 264 dose-dependently elevated the lyso-PS content of macrophages and the mice brain. We also found the macrophages and the mice treated with DO 264 showed augmented immune responses. These results support an immunostimulatory function for the ABHD12-(lyso)-PS pathway that can be pharmacologically controlled with selective ABHD12 inhibitors.