Research Progress of Mitochondrial ClpP Agonists against Tumor
Mitochondria are organelles important for performing and coordinating a wide range of metabolic and vital activities within the cell.Mitochondrial dysfunction severely affects the cell fitness,leading to a series of illness such as neurodegenerative diseases,cardiovascular diseases,and tumorigenesis.The accumulation of damaged or misfolded proteins in mitochondria will trigger integra-tion stress responses and unfolded protein responses.Mitochondrial can coordinate protein homeostasis under the quality control sys-tem formed by a bunch of protease within mitochondrial matrix which can recognize and hydrolyze abnormal proteins to maintain the health of proteome in mitochondrial.In particular,the mitochondrial serine protease ClpP maintains normal mitochondrial function by degrading abnormal unfolded or misfolded proteins with the help of its molecular chaperone,ClpX.Numerous studies have shown that ClpP is highly expressed in many different tumor cells.Disturbance of the expression of ClpP in many sorts of tumor cells including solid tumor and AML will lead to the death of tumor cells.It was also found that ClpP is required for tumor cell proliferation,migra-tion and invasion.Therefore,ClpP can be used as a potential drug therapy target for patients.In recent years,the therapeutic effect of small molecules by targeting and activating ClpP has achieved remarkable progress in different tumor type of xenograft mouse models.Among them,Imipridone analogues,represented by ONC201 with remarkable anti-tumor effects and high safety,have been approved for clinical phase Ⅲ trials.In this review,the authors provide a comprehensive overview of the structure,physiological function,and latest reported studies related to how small molecule agonists of ClpP function as a potent anti-tumor compound and its impact on cell signal pathway.Finally,the authors discuss the opportunities and challenges of new small molecule compounds which can selectively bind and activate homo sapiens ClpP while have little effect on the bacterial ClpP.
ClpP proteaseQuality control of mitochondrionAgonistTumor therapyOXPHOSUPRmt
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