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Stuart, S D, et al. A strategically designed small molecule attacks alpha-ketoglutarate dehydrogenase in tumor cells through a redox process. Cancer Metab, 2014. 2(1):4.

Synopsis

There is an emerging recognition that targeting cancer metabolism warrants further exploration. Investigators at Cornerstone Pharmaceuticals had previously reported that CPI-613 inactivated the lipoate-dependent complex (PDH) to induce tumor growth inhibition in human xenograft models. In addition, early clinical studies have shown anecdotal indications of efficacy. Therefore, understanding the extent of CPI-613’s effects on metabolic pathways may bolster future strategies for targeting cancer metabolism and the design of clinical trials. To achieve this, Metabolomics was performed on cell lines treated with CPI-613. Results showed that CPI-613 also impairs a second lipoate-dependent complex, KGDH. Likely not coincidental to the efficacy, PDH and KGDH are the 2 major thoroughfares for carbon flow into mitochondrial metabolism. Blocking these carbon highways produces a catastrophic inhibition of tumor mitochondrial metabolism and cell death. Collectively these results show that the simultaneous attack on multiple metabolic features may be a viable clinical strategy.

Metabolon results led to:

•    Key insights into drug mechanism of action (MOA)

•    A novel example for the potential of targeting multiple tumor nodes simultaneously

 

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