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Published on: September 30, 2016
IMP075 targeting ClpP for colon cancer therapy in vivo and in vitro
Jiangnan Zhang1, Baozhu Luo1, Jing Sui1
1State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China.
Abstract:
ONC201 is a well-known caseinolytic protease (ClpP)activator with established benefits against multiple tumors, including colorectal cancer (CRC). In this study, we investigated the anticancer effects and associated mechanisms of the ClpP agonist IMP075, derived from ONC201. Acute toxicity and CCK-8 assayswere employed to determine the safety of IMP075. The effectiveness of IMP075 was investigated in HCT116 cells and a mouse xenograft tumor model. Additionally, the properties of IMP075 were evaluated by pharmacokinetic,CYP inhibition, and hERG inhibition assays. Finally, isothermal titration calorimetry (ITC), differential scanning fluorimetry (DSF), cellular thermal shift assay (CETSA), molecular dynamics simulations, point mutations, and shRNA experiments were employed to elucidate the potential mechanism of IMP075. Compared with ONC201, IMP075 exhibited similar toxicity and improved antitumor effects in vitro and in vivo. Interestingly, the affinity and agonistic effects of IMP075 on ClpP were superior to ONC201, which allowed IMP075 to disrupt respiratory chain integrity at lower doses in HCT116 cells, leading to mitochondrial dysfunction. Furthermore, molecular dynamics simulations demonstrate that IMP075 forms two pairs of hydrogen bonds with ClpP, maintaining ClpP in an agonistic state. Importantly, the antiproliferative activity of IMP075 significantly decreased following ClpP knockdown. Our findings substantiate that IMP075 exerts excellent antitumor effects against CRC by activating ClpP-mediated impairment of mitochondrial function. Due to its superior properties, IMP075 appears to be have huge prospects for application.
Insights
IMP075, a novel caseinolytic protease (ClpP) activator, shows enhanced anti-colorectal cancer effects by disrupting mitochondrial function. This ClpP agonist demonstrates significant promise for CRC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- ONC201 is a known caseinolytic protease (ClpP) activator with anti-cancer properties.
- Colorectal cancer (CRC) remains a significant global health challenge requiring novel therapeutic strategies.
Purpose of the Study:
- To investigate the anti-cancer effects and mechanisms of IMP075, a ClpP agonist derived from ONC201.
- To compare the efficacy and safety of IMP075 against ONC201 in colorectal cancer models.
Main Methods:
- Assessed IMP075 safety and efficacy using CCK-8 assays, HCT116 cells, and a mouse xenograft model.
- Evaluated IMP075 properties via pharmacokinetic, CYP, and hERG inhibition assays.
- Elucidated mechanisms using ITC, DSF, CETSA, molecular dynamics, mutations, and shRNA.
Main Results:
- IMP075 demonstrated similar toxicity but improved in vitro and in vivo anti-tumor effects compared to ONC201.
- IMP075 exhibited superior affinity and agonistic effects on ClpP, disrupting mitochondrial function at lower doses.
- Molecular dynamics confirmed IMP075's interaction with ClpP, maintaining its agonistic state and leading to mitochondrial dysfunction.
Conclusions:
- IMP075 effectively treats colorectal cancer by activating ClpP, impairing mitochondrial function.
- IMP075's superior properties suggest significant potential for clinical application in CRC therapy.
