mTOR inhibition via displacement of phosphatidic acid induces enhanced cytotoxicity specifically in cancer cells

The mammalian target of rapamycin (mTOR) is a central regulator of cell growth and is highly activated in cancer cells to allow rapid tumor growth. The use of mTOR inhibitors as anti-cancer therapy has been approved for some types of tumors, albeit with modest results. We recently reported the synthesis of ICSN3250, a halitulin-analogue with enhanced cytotoxicity. We report here that ICSN3250 is a specific mTOR inhibitor that operates through a mechanism distinct from those described for previous mTOR inhibitors. ICSN3250 competed with and displaced phosphatidic acid from the FRB domain in mTOR, thus preventing mTOR activation and leading to cytotoxicity. Docking and molecular dynamics simulations evidenced not only the high conformational plasticity of the FRB domain, but also the specific interactions of both ICSN3250 and phosphatidic acid with the FRB domain in mTOR. Furthermore, ICSN3250 toxicity was shown to act specifically in cancer cells, as non-cancer cells showed up to 100-fold less sensitivity to ICSN3250, in contrast to other mTOR inhibitors which did not show selectivity. Thus, our results define ICSN3250 as a new-class of mTOR inhibitors that specifically targets cancer cells.

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