文献类型：期刊文献

英文题名：Trilogy of drug repurposing for developing cancer and chemotherapy-induced heart failure co-therapy agent

作者：Chen, Xin[1,3];Mu, Xianggang[1];Ding, Lele[2];Wang, Xi[2];Mao, Fei[1];Wei, Jinlian[1];Liu, Qian[2];Xu, Yixiang[1];Ni, Shuaishuai[2];Jia, Lijun[2];Li, Jian[1]

机构：[1]East China Univ Sci & Technol, Shanghai Frontiers Sci Ctr Optogenet Tech Cell Met, Frontiers Sci Ctr Materiobiol & Dynam Chem, Shanghai Key Lab New Drug Design,Sch Pharm,State K, Shanghai 200237, Peoples R China;[2]Shanghai Univ Tradit Chinese Med, Longhua Hosp, Canc Inst, Shanghai 200032, Peoples R China;[3]Jinan Univ, Coll Pharm, Guangzhou 510632, Peoples R China

年份：2024

卷号：14

期号：2

起止页码：729

外文期刊名：ACTA PHARMACEUTICA SINICA B

收录：;WOS:【SCI-EXPANDED(收录号:WOS:001170500000001)】；

基金：This work was supported by the National Natural Science Foundation of China (Grant Nos. 22177076, 81820108022, 22037002) , the Shanghai Frontier Science Center of Optogenetic Techniques for Cell Metabolism (2021 Sci & Tech 03-28, China) , Shanghai Frontiers Science Center of Disease and Syndrome Biology of Inflammatory Cancer Transformation (2021KJ03-12, China) , the Innovative Research Team of High-level Local Universities in Shanghai (SHSMU-ZDCX20212702, China) , and the Chinese Special Fund for State Key Laboratory of Bioreactor Engineering (2060204) , Innovation Program of Shanghai Municipal Education Commission (2019-01-07-00-10-E00056, 2021-01-07-00-02-E00104, China) , the Scientific and Technological Innovation Action Plan of Science and Technology Commission of Shanghai (20JC1411300, China) . We are also grateful for the help of Prof. Jin Huang, Prof. Yi Sun, Dr. Qing Yu, and Dr. Zhiguo Hu.

语种：英文

外文关键词：Anticancer; Heart failure; Complication; Drug repurposing; Bi-functional drug

摘要：Chemotherapy-induced complications, particularly lethal cardiovascular diseases, pose significant challenges for cancer survivors. The intertwined adverse effects, brought by cancer and its complication, further complicate anticancer therapy and lead to diminished clinical outcomes. Simple supplementation of cardioprotective agents falls short in addressing these challenges. Developing bifunctional co-therapy agents provided another potential solution to consolidate the chemotherapy and reduce cardiac events simultaneously. Drug repurposing was naturally endowed with co-therapeutic potential of two indications, implying a unique chance in the development of bi-functional agents. Herein, we further proposed a novel "trilogy of drug repurposing" strategy that comprises function-based, targetfocused, and scaffold-driven repurposing approaches, aiming to systematically elucidate the advantages of repurposed drugs in rationally developing bi-functional agent. Through function-based repurposing, a cardioprotective agent, carvedilol (CAR), was identified as a potential neddylation inhibitor to suppress lung cancer growth. Employing target-focused SAR studies and scaffold-driven drug design, we synthesized 44 CAR derivatives to achieve a balance between anticancer and cardioprotection. Remarkably, optimal derivative 43 displayed promising bi-functional effects, especially in various self -established heart failure mice models with and without tumor -bearing. Collectively, the present study validated the practicability of the "trilogy of drug repurposing" strategy in the development of bi-functional co - therapy agents. 2024 The Authors. Published by Elsevier B.V. on behalf of Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. This is an open access article under the CC BY -NC - ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).