Discovery of orally active and serine-targeting covalent inhibitors against hCES2A for ameliorating irinotecan-triggered gut toxicity.
10.1016/j.apsb.2025.08.007
- Author:
Ya ZHANG
1
;
Yufan FAN
1
;
Yunqing SONG
1
;
Guanghao ZHU
1
;
Xinjuan LI
2
;
Jian HUANG
1
;
Xinrui GUO
3
;
Changhai LUAN
1
;
Dongning KANG
3
;
Lu CHEN
1
;
Zhangping XIAO
4
;
Zhaobin GUO
1
;
Hairong ZENG
1
;
Dapeng CHEN
1
;
Zhipei SANG
1
;
Guangbo GE
1
Author Information
1. State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine; Shanghai Frontiers Science Center of TCM Chemical Biology; Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
2. Key Laboratory of Tropical Biological Resources of Ministry of Education and One Health Institute, Hainan One Health Key Laboratory, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China.
3. Dalian Medical University, Dalian 116044, China.
4. Department of Chemistry, Imperial College London W12 0BZ, UK.
- Publication Type:Journal Article
- Keywords:
Carbamates;
Covalent inhibitors;
Donepezil derivatives;
Drug repurposing;
Human carboxylesterase 2 (hCES2A);
Irinotecan-triggered gut toxicity (ITGT);
Structure-based drug design (SBDD);
Structure–activity relationship (SAR)
- From:
Acta Pharmaceutica Sinica B
2025;15(10):5312-5326
- CountryChina
- Language:English
-
Abstract:
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.
