Discovery of a Novel Serine-Targeting Covalent Inhibitor against HCES2A for Treating Drug-induced Diarrhea and Ulcerative Colitis

Mammalian
carboxylesterases play an important role in
the hydrolysis
of both endogenous substrates and xenobiotics bearing ester or amide
bond(s). We previously reported that bysspectin A and its derivative
LC-20W were potent reversible hCES2A inhibitors. Here, a series of
bysspectin A derivatives were designed and synthesized using LC-20W
as the leading compound. Compound 9d was identified as
a potent serine-targeting covalent inhibitor of hCES2A (IC50 = 0.12 nM), which was much more potent than that of LC-20W. Further
chemoproteomics and docking simulations showed that 9d could selectively modify hCES2A at the catalytic serine (Ser228),
thereby blocking its catalytic activity. Notably, 9d showed
good cell-membrane permeability and was capable of inhibiting intracellular
hCES2A in living cells. In vivo tests showed that 9d significantly alleviates irinotecan-induced diarrhea and
dextran sulfate sodium-induced colitis. Collectively, a novel serine-targeting
covalent inhibitor against hCES2A was developed, offering a promising
candidate for treating drug-induced diarrhea and ulcerative colitis.