Abstract

Activity-based probes (ABPs) are essential tools to study and modulate the dynamics of biological systems. ABPs have been instrumental to profile the activity of serine hydrolases in diverse and complex proteomes, as well as to screen for selective inhibitors of this large family of enzymes that have diverse roles in key cellular processes. A major challenge in developing robust ABPs is to identify appropriate warheads and chemistries to modulate the selectivity towards target serine hydrolases. This presentation will cover our recent approaches to identify selective ABPs and inhibitors for serine hydrolases. We will describe how our strategy using warheads based on four-membered rings enabled the discovery of selective and potent inhibitors of dipeptidyl peptidases DPP8 and DPP9, two serine hydrolases that play key roles in the immune response and tumorigenesis.