Discovery of CLPP-1071 as an Exceptionally Potent and Orally Efficacious Human ClpP Activator with Strong In Vivo Antitumor Activity
<i>Human sapiens</i> 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 <b>ONC201</b> in Phase III clinical trials. Through structural optimization of the lead compound, the most optimal compound, <b>CLPP-1071</b>, exhibited exceptionally potent ClpP agonistic activity (EC<sub>50</sub> = 23.5 nM, 107.1-fold stronger than <b>ONC201</b>) and inhibited the proliferation of HL60 cells (IC<sub>50</sub> = 4.6 nM, 169.2-fold stronger than <b>ONC201</b>). <b>CLPP-1071</b> possesses good pharmacokinetic properties and effectively prolongs the lifespan in the MOLM13 and HL60 xenograft models in mice through oral administration. <b>CLPP-1071</b> is the most potent and orally efficacious ClpP activator reported to date.
Authors
- Xinyi Lin (ORCID: https://orcid.org/0000-0002-9075-5364)
- Renzhao Gui
- Qi Huang (ORCID: https://orcid.org/0000-0003-1073-7471)
- Mingliang Wang
- Linghao Hu (ORCID: https://orcid.org/0000-0002-3770-2984)
- Xiaobei Hu (ORCID: https://orcid.org/0000-0002-7765-1771)
- Lei Xu (ORCID: https://orcid.org/0000-0003-2240-0737)
- Zan Huang (ORCID: https://orcid.org/0000-0001-5623-6950)
- Mingyue Zheng (ORCID: https://orcid.org/0000-0002-3323-3092)
- Beijing Chen (ORCID: https://orcid.org/0000-0002-2506-0427)
- Yubo Zhou (ORCID: https://orcid.org/0000-0002-0694-3697)
- Huicong Ma (ORCID: https://orcid.org/0000-0003-3678-3476)
- Jia Li (ORCID: https://orcid.org/0000-0003-3145-2811)
- Mingyang Sun (ORCID: https://orcid.org/0000-0003-3181-6793)
- Dan Teng
- Chun Zhang (ORCID: https://orcid.org/0000-0001-7041-6958)
Institutions
- Guiyang Medical University (CN)
- Zunyi Medical University (CN)
- Chinese Academy of Sciences (CN)
- Fudan University (CN)
- Shanghai Institute of Materia Medica (CN)
- State Key Laboratory of Chemical Engineering (CN)
- Southern Medical University (CN)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-11-22
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c01605
- Citations
- 10
- Primary Topic
- ATP Synthase and ATPases Research
- Type
- article
- Field-Weighted Citation Impact
- 2.34
Funders
- Shanghai Science and Technology Development Foundation
- National Natural Science Foundation of China
- China Postdoctoral Science Foundation