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Discovery of CLPP-1071 as an Exceptionally Potent and Orally Efficacious Human ClpP Activator with Strong In Vivo Antitumor Activity

Year: 2024
Type: article
Abstract: High Resolution Image Download MS PowerPoint Slide Human sapiens 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 ONC201 in Phase III clinical trials. Through structural optimization of the lead compound, the most optimal compound, CLPP-1071, exhibited exceptionally potent ClpP agonistic activity (EC 50 = 23.5 nM, 107.1-fold stronger than ONC201 ) and inhibited the proliferation of HL60 cells (IC 50 = 4.6 nM, 169.2-fold stronger than ONC201 ). CLPP-1071 possesses good pharmacokinetic properties and effectively prolongs the lifespan in the MOLM13 and HL60 xenograft models in mice through oral administration. CLPP-1071 is the most potent and orally efficacious ClpP activator reported to date.
DOI: 10.1021/acs.jmedchem.4c01605
Authors: Beijing Chen, Mingyang Sun, Chun Zhang, Qi Huang, Dan Teng, Linghao Hu, Huicong Ma, Xinyi Lin, Zan Huang, Renzhao Gui, Xiaobei Hu, Lei Xu, Mingyue Zheng, Yubo Zhou, Jia Li, Mingliang Wang
Institutions: Guiyang Medical University, Chinese Academy of Sciences, Shanghai Institute of Materia Medica, Zunyi Medical University, Fudan University, Southern Medical University, State Key Laboratory of Drug Research
Language: English
Open Access status: hybrid
Estimated APC paid: $4,500
OpenAlex ID: W4404616745
FWCI: 1.766
Cites: 54
Cited by: 15
Related to: 10