Chen Beijing, Sun Mingyang, Zhang Chun, Huang Qi, Teng Dan, Hu Linghao, Ma Huicong, Lin Xinyi, Huang Zan, Gui Renzhao, Hu Xiaobei, Xu Lei, Zheng Mingyue, Zhou Yubo, Li Jia, Wang Mingliang
Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Tsuihang New District, Zhongshan 528400, Guangdong, China.
School of Pharmacy, Guizhou Medical University, Guiyang 550014, China.
J Med Chem. 2024 Dec 12;67(23):21009-21029. doi: 10.1021/acs.jmedchem.4c01605. Epub 2024 Nov 22.
caseinolytic protease P (ClpP) is essential for maintaining mitochondrial proteome homeostasis, and its activation is increasingly recognized as a promising cancer therapy strategy. Herein, based on structure-guided drug design, we discovered a series of potent ClpP activators by introducing a methyl group to the imipridone scaffold of the ClpP activator in Phase III clinical trials. Through structural optimization of the lead compound, the most optimal compound, , exhibited exceptionally potent ClpP agonistic activity (EC = 23.5 nM, 107.1-fold stronger than ) and inhibited the proliferation of HL60 cells (IC = 4.6 nM, 169.2-fold stronger than ). possesses good pharmacokinetic properties and effectively prolongs the lifespan in the MOLM13 and HL60 xenograft models in mice through oral administration. is the most potent and orally efficacious ClpP activator reported to date.
酪蛋白水解蛋白酶P（ClpP）对于维持线粒体蛋白质组稳态至关重要，其激活日益被认为是一种有前景的癌症治疗策略。在此，基于结构导向药物设计，我们通过在处于III期临床试验的ClpP激活剂的咪喹酮支架上引入一个甲基，发现了一系列强效的ClpP激活剂。通过对先导化合物进行结构优化，最优化合物表现出异常强效的ClpP激动活性（EC = 23.5 nM，比强107.1倍），并抑制HL60细胞增殖（IC = 4.6 nM，比强169.2倍）。具有良好的药代动力学性质，通过口服给药可有效延长小鼠MOLM13和HL60异种移植模型的寿命。是迄今为止报道的最有效且口服有效的ClpP激活剂。
