Human carboxylesterase 2A(hCES2A)plays pivotal roles in prodrug activation and hydrolytic metabolism of ester-bearing chemicals.Targeted inhibition of intestinal hCES2A represents a feasible strategy to mitigate irino...Human carboxylesterase 2A(hCES2A)plays pivotal roles in prodrug activation and hydrolytic metabolism of ester-bearing chemicals.Targeted inhibition of intestinal hCES2A represents a feasible strategy to mitigate irinotecan-triggered gut toxicity(ITGT),but the orally active,selective,and efficacious hCES2A inhibitors are rarely reported.Here,a novel drug-like hCES2A inhibitor was developed via three rounds of structure-based drug design(SBDD)and structural optimization.Initially,donepezil was identified as a moderate hCES2A inhibitor from 2000 US Food and Drug Administration(FDA)-approved drugs.Following two rounds of SBDD and structural optimization,a donepezil derivative(B7)was identified as a strong reversible hCES2A inhibitor.Subsequently,nine B7 carbamates were rationally designed,synthesized and biologically assayed.Among all synthesized carbamates,C3 showed the most potent time-dependent inhibition on hCES2A(IC50=0.56 nmol/L),excellent specificity and favorable drug-like properties.C3 could covalently modify the catalytic serine of hCES2A with high selectivity,while this agent also showed favorable safety profiles,high intestinal exposure,and impressive effects for ameliorating ITGT in both human intestinal organoids and tumor-bearing mice.Collectively,this study showcases a rational strategy for developing drug-like and serine-targeting covalent inhibitors against target serine hydrolase(s),while C3 emerges as a promising orally active drug candidate for ameliorating ITGT.展开更多
基金supported by the National Natural Science Foundation of China(Nos.82104281,82273897,and 22367007)China Postdoctoral Science Foundation(Nos.2022M712153,and 2023M742380)+3 种基金The Fundamental Research Funds for Hainan University(KYQD(ZR)23002,China)Hainan Provincial Natural Science Foundation of China(824RC500)PhD Program in Key Fields at Shanghai University of Traditional Chinese Medicine(GJ2023004,China)Liaoning Province Science and Technology Plan Alliance Fund project(2024-BSLH-041,China).
文摘Human carboxylesterase 2A(hCES2A)plays pivotal roles in prodrug activation and hydrolytic metabolism of ester-bearing chemicals.Targeted inhibition of intestinal hCES2A represents a feasible strategy to mitigate irinotecan-triggered gut toxicity(ITGT),but the orally active,selective,and efficacious hCES2A inhibitors are rarely reported.Here,a novel drug-like hCES2A inhibitor was developed via three rounds of structure-based drug design(SBDD)and structural optimization.Initially,donepezil was identified as a moderate hCES2A inhibitor from 2000 US Food and Drug Administration(FDA)-approved drugs.Following two rounds of SBDD and structural optimization,a donepezil derivative(B7)was identified as a strong reversible hCES2A inhibitor.Subsequently,nine B7 carbamates were rationally designed,synthesized and biologically assayed.Among all synthesized carbamates,C3 showed the most potent time-dependent inhibition on hCES2A(IC50=0.56 nmol/L),excellent specificity and favorable drug-like properties.C3 could covalently modify the catalytic serine of hCES2A with high selectivity,while this agent also showed favorable safety profiles,high intestinal exposure,and impressive effects for ameliorating ITGT in both human intestinal organoids and tumor-bearing mice.Collectively,this study showcases a rational strategy for developing drug-like and serine-targeting covalent inhibitors against target serine hydrolase(s),while C3 emerges as a promising orally active drug candidate for ameliorating ITGT.
