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Discovery of CLPP-1071 as an Exceptionally Potent and Orally Efficacious Human ClpP Activator with Strong In Vivo
Beijing Chen1,2, Mingyang Sun1, Chun Zhang1,3
1Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Tsuihang New District, Zhongshan 528400, Guangdong, China.
Abstract:
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 (EC50 = 23.5 nM, 107.1-fold stronger than ONC201) and inhibited the proliferation of HL60 cells (IC50 = 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.
Insights
Researchers discovered CLPP-1071, a potent activator of human caseinolytic protease P (ClpP), a key target for cancer therapy. This new compound shows enhanced efficacy and oral bioavailability in preclinical models.
Area of Science:
- Biochemistry
- Mitochondrial Biology
- Drug Discovery
Background:
- Mitochondrial proteome homeostasis is crucial for cell function.
- Activation of caseinolytic protease P (ClpP) is a promising cancer therapy strategy.
- ONC201 is a known ClpP activator currently in Phase III clinical trials.
Purpose of the Study:
- To discover novel and more potent ClpP activators.
- To optimize the imipridone scaffold for enhanced ClpP agonistic activity.
- To evaluate the therapeutic potential of optimized compounds in cancer models.
Main Methods:
- Structure-guided drug design.
- Synthesis and structural optimization of imipridone derivatives.
- Biochemical assays to measure ClpP activation (EC50).
- Cell proliferation assays (IC50) in cancer cell lines.
- In vivo pharmacokinetic and efficacy studies in mouse xenograft models.
Main Results:
- CLPP-1071, a novel imipridone derivative, was identified as a potent ClpP activator.
- CLPP-1071 demonstrated significantly higher ClpP agonistic activity (EC50 = 23.5 nM) and anti-proliferative effects (IC50 = 4.6 nM) compared to ONC201.
- CLPP-1071 exhibited favorable pharmacokinetic properties and prolonged survival in mouse models of leukemia (MOLM13 and HL60) upon oral administration.
Conclusions:
- CLPP-1071 represents a highly potent and orally efficacious ClpP activator.
- The findings support the development of CLPP-1071 as a potential new cancer therapeutic agent.
- Structure-guided optimization of ClpP activators can yield compounds with improved potency and drug-like properties.
