更新于：2024-11-01

FXR x CES2

更新于：2024-11-01

基本信息

关联

项与 FXR x CES2 相关的药物

LE-77

靶点

CES2 x FXR

作用机制

CES2 调节剂 [+1]

在研机构

广东药科大学

原研机构

广东药科大学

在研适应症

腹泻

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 FXR x CES2 相关的临床结果

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100 项与 FXR x CES2 相关的转化医学

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0 项与 FXR x CES2 相关的专利（医药）

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项与 FXR x CES2 相关的文献（医药）

2024-12-01·Bioorganic Chemistry

Discovery of the FXR/CES2 dual modulator LE-77 for the treatment of irinotecan-induced delayed diarrhea

Article

作者: Li, Zheng ; Wang, Wenxin ; Sun, Lidan ; Liu, Yuxia ; Zhang, Luyong ; Cao, Zhijun ; Yang, Zhongcheng

Irinotecan (CPT-11) is a widely utilized topoisomerase I inhibitor in the treatment of colorectal cancer and other malignant tumors. However, severe and even life-threatening dose-limiting toxicity-delayed diarrhea affects the clinical application of CPT-11. The standard treatment for CPT-11-induced delayed diarrhea is prompt use of loperamide (LPA), however LPA can also cause constipation, diarrhea and even intestinal obstruction and has a high failure rate. Carboxylesterase 2 (CES2) is the main enzyme in the intestinal transformation of CPT-11, which can convert CPT-11 into toxic metabolite SN-38 and produce intestinal toxicity. Inhibiting CES2 activity can block the hydrolysis process of CPT-11 in the intestine and reduce SN-38 accumulation. Additionally, Farnesoid X receptor (FXR) agonists have anti-inflammatory, anti-secretory, and protective functions on intestinal barrier integrity that could potentially alleviate diarrhea. In this study, we investigated for the first time the anti-delayed diarrhea effect of FXR agonists, and the first time identified LE-77 as a potent dual modulator that activates FXR and inhibits CES2 through high-throughput screening. In the CPT-11-induced delayed diarrhea model, LE-77 demonstrated a dual modulator mechanism by activating FXR and inhibiting CES2, thereby reducing the accumulation of SN-38 in the intestine, alleviating intestinal inflammation, preserving intestinal mucosal integrity, and ultimately alleviating delayed diarrhea.

Biomedicines

Pharmacological Properties and Molecular Targets of Alisol Triterpenoids from Alismatis Rhizoma

Review

作者: Bailly, Christian

More than 100 protostane triterpenoids have been isolated from the dried rhizomes of Alisma species, designated Alismatis rhizoma (AR), commonly used in Asian traditional medicine to treat inflammatory and vascular diseases. The main products are the alisols, with the lead compounds alisol-A/-B and their acetate derivatives being the most abundant products in the plant and the best-known bioactive products. The pharmacological effects of Ali-A, Ali-A 24-acetate, Ali-B, Ali-B 23-acetate, and derivatives have been analyzed to provide an overview of the medicinal properties, signaling pathways, and molecular targets at the origin of those activities. Diverse protein targets have been proposed for these natural products, including the farnesoid X receptor, soluble epoxide hydrolase, and other enzymes (AMPK, HCE-2) and functional proteins (YAP, LXR) at the origin of the anti-atherosclerosis, anti-inflammatory, antioxidant, anti-fibrotic, and anti-proliferative activities. Activities were classified in two groups. The lipid-lowering and anti-atherosclerosis effects benefit from robust in vitro and in vivo data (group 1). The anticancer effects of alisols have been largely reported, but, essentially, studies using tumor cell lines and solid in vivo data are lacking (group 2). The survey shed light on the pharmacological properties of alisol triterpenoids frequently found in traditional phytomedicines.