Probe Development Efforts to Identify Novel Inhibitors of ABHD10

The Scripps Research Institute Molecular Screening Center (SRIMSC) recently completed a fluorescence-polarization activity-based protein profiling (fluopol-ABPP) high throughput screening (HTS) campaign to identify inhibitors of protein phosphatase methylesterase-1 (PME-1). This campaign unveiled a phenomenal class of potent and selective inhibitors, the aza-beta lactams (ABLs), one of which, ML174, showed exceptional and potency and selectivity for PME-1. During medicinal chemistry investigation of the ABLs for PME-1, we observed that one of the common anti-targets was the uncharacterized serine hydrolase abhydrolase domain containing protein 10 (ABHD10). This fortuitous discovery of inhibitor leads was of particular interest to us, as we had recently uncovered some exciting evidence that ABHD10 functions as a lipase . A principle goal of post-genomic research is to elucidate the molecular and cellular roles of uncharacterized enzymes like ABHD10, an investigation which profits significantly from chemical tools for precise regulation of enzyme activity. Given that no selective inhibitors of ABHD10 have yet been reported in the literature, we completed a medicinal chemistry campaign to optimize an ABL probe for ABHD10, which is presented herein as ML257. This probe is highly potent against ABHD10 (IC50 = 17 nM), (IC50 = 28 nM), and (active at 25 mg/kg, i.p., in mice), and exhibits remarkable selectivity among 40+ other serine hydrolases. Importantly, this probe demonstrates the potential for exploiting fortuitous inhibitor leads for orthogonal, “anti-target” enzymes, thus maximizing the benefits of a single HTS campaign, and highlights the “privileged” nature of the ABL scaffold for serine hydrolase inhibitor development.