Discovery of 5-(Piperidin-4-yl)-1,2,4-oxadiazole Derivatives as a New Class of Human Caseinolytic Protease P Agonists for the Treatment of Hepatocellular Carcinoma
机构：[1]Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.四川大学华西医院[2]Institute of Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China.四川大学华西医院
Chemical agonism of human caseinolytic protease P (HsClpP) is increasingly being recognized as a potential anticancer strategy due to its critical role in maintaining mitochondrial homeostasis. We unveil the discovery of 5-(piperidin-4-yl)-1,2,4-oxadiazole derivatives as a novel class of HsClpP agonists and demonstrate for the first time the application of HsClpP agonists in the treatment of hepatocellular carcinoma (HCC) (Pace, A.; Pierro, P. The new era of 1,2,4-oxadiazoles. Org. Biomol. Chem. 2009, 7 (21), 4337-4348). Compound SL44 exhibited potent HsClpP agonistic activity in the α-casein hydrolysis assay (EC50 = 1.30 μM) and inhibited the proliferation of HCCLM3 cells (IC50 = 3.1 μM, 21.4-fold higher than hit ADX-47273). Mechanistically, SL44 induces degradation of respiratory chain complex subunits and leads to apoptosis in HCC cells. In vivo results demonstrated that SL44 has potent tumor growth inhibitory activity and has a superior safety profile compared to the kinase inhibitor sorafenib. Overall, we developed a novel class of HsClpP agonists that can potentially be used for the treatment of HCC.
基金：
National Natural
Science Foundation of China (No. 82373916 and No.
82173861). We extend our sincere appreciation to the
Engineering Experimental Teaching Center, School of Chemical Engineering at Sichuan University, for generously providing the
Nano ITC 200 microcalorimeter. This crucial support has been
instrumental in facilitating our Isothermal Titration Calorimetry
(ITC) assays.
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2023]版：
大类|1 区医学
小类|1 区药物化学
最新[2023]版：
大类|1 区医学
小类|1 区药物化学
第一作者：
第一作者机构：[1]Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
共同第一作者：
通讯作者：
通讯机构：[1]Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.[2]Institute of Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China.
推荐引用方式(GB/T 7714)：
Liu Song,Sui Jing,Luo Baozhu,et al.Discovery of 5-(Piperidin-4-yl)-1,2,4-oxadiazole Derivatives as a New Class of Human Caseinolytic Protease P Agonists for the Treatment of Hepatocellular Carcinoma[J].Journal Of Medicinal Chemistry.2024,doi:10.1021/acs.jmedchem.4c00080.
APA：
Liu Song,Sui Jing,Luo Baozhu,Zhang Jiangnan,Xiang Xinrong...&Liu Jie.(2024).Discovery of 5-(Piperidin-4-yl)-1,2,4-oxadiazole Derivatives as a New Class of Human Caseinolytic Protease P Agonists for the Treatment of Hepatocellular Carcinoma.Journal Of Medicinal Chemistry,,
MLA：
Liu Song,et al."Discovery of 5-(Piperidin-4-yl)-1,2,4-oxadiazole Derivatives as a New Class of Human Caseinolytic Protease P Agonists for the Treatment of Hepatocellular Carcinoma".Journal Of Medicinal Chemistry .(2024)
医学