期刊
ACS CHEMICAL BIOLOGY
卷 14, 期 5, 页码 1020-1029出版社
AMER CHEMICAL SOC
DOI: 10.1021/acschembio.9b00222
关键词
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资金
- NIH [R01 AI103311, 5 T32 GM007040]
- Lineberger University Cancer Research Grant (UNC)
- Russian Science Foundation [19-75-20145]
- New York-Presbyterian Brooklyn Methodist Hospital
- [NIHP30 CA016086]
- [R01 CA199064]
- Russian Science Foundation [19-75-20145] Funding Source: Russian Science Foundation
ONC201 is a first-in-class imipridone molecule currently in clinical trials for the treatment of multiple cancers. Despite enormous clinical potential, the mechanism of action is controversial. To investigate the mechanism of ONC201 and identify compounds with improved potency, we tested a series of novel ONC201 analogues (TR compounds) for effects on cell viability and stress responses in breast and other cancer models. The TR compounds were found to be similar to 50-100 times more potent at inhibiting cell proliferation and inducing the integrated stress response protein ATF4 than ONC201. Using immobilized TR compounds, we identified the human mitochondrial caseinolytic protease P (CIpP) as a specific binding protein by mass spectrometry. Affinity chromatography/drug competition assays showed that the TR compounds bound CIpP with similar to 10-fold higher affinity compared to ONC201. Importantly, we found that the peptidase activity of recombinant ClpP was strongly activated by ONC201 and the TR compounds in a dose- and time-dependent manner with the TR compounds displaying a similar to 10-100 fold increase in potency over ONC201. Finally, siRNA knockdown of ClpP in SUM159 cells reduced the response to ONC201 and the TR compounds, including induction of CHOP, loss of the mitochondrial proteins (TEAM, TUFM), and the cytostatic effects of these compounds. Thus, we report that ClpP directly binds ONC201 and the related TR compounds and is an important biological target for this class of molecules. Moreover, these studies provide, for the first time, a biochemical basis for the difference in efficacy between ONC201 and the TR compounds.
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