Selective Inhibitor of Platelet-Activating Factor Acetylhydrolases 1b2 and 1b3 That Impairs Cancer Cell Survival

Platelet-activating factor acetylhydrolases
(PAFAHs) 1b2 and 1b3
are poorly characterized serine hydrolases that form a complex with
a noncatalytic protein (1b1) to regulate brain development, spermatogenesis,
and cancer pathogenesis. Determining physiological substrates and
biochemical functions for the PAFAH1b complex would benefit from selective
chemical probes that can perturb its activity in living systems. Here,
we report a class of tetrahydropyridine reversible inhibitors of PAFAH1b2/3
discovered using a fluorescence polarization-activity-based protein
profiling (fluopol-ABPP) screen of the NIH 300 000+ compound
library. The most potent of these agents, P11, exhibited IC50 values of ∼40 and 900 nM for PAFAH1b2 and 1b3, respectively.
We confirm selective inhibition of PAFAH1b2/3 in cancer cells by P11
using an ABPP protocol adapted for in situ analysis
of reversible inhibitors and show that this compound impairs tumor
cell survival, supporting a role for PAFAH1b2/3 in cancer.