AI-Driven Discovery of Highly Specific and Efficacious hCES2A Inhibitors for Ameliorating Irinotecan-Triggered Gut Toxicity

The anticancer agent irinotecan often induces severe
delayed-onset
diarrhea, inhibiting human carboxylesterase 2A (hCES2A) can significantly
alleviate irinotecan-triggered gut toxicity (ITGT). This work presents
an efficient workflow for de novo design and developing
novel efficacious hCES2A inhibitors. A well-training machine learning
model identified scaffold-14 as a lead compound, while
compound 14n was developed as a novel time-dependent
hCES2A inhibitor (IC50 = 0.04 nM) following three rounds
of structural optimization. The covalent binding modes and inactivation
mechanisms of 14n were elucidated by nanoLC-MS/MS-based
chemoproteomics and covalent docking simulations. Notably, 14n showed excellent selectivity, good cell-membrane permeability, favorable
drug-like properties, and potent inhibition on intracellular hCES2A. In vivo tests demonstrated that 14n was orally
active, showing favorable safety profiles and impressive ameliorative
effects on ITGT in tumor-bearing mice. Collectively, this work showcases
a high-efficient AI-driven strategy for developing novel efficacious
hCES2A inhibitors, while 14n emerges as a promising candidate
for alleviating ITGT.