期刊
CANCER RESEARCH
卷 78, 期 18, 页码 5384-5397出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-18-0232
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资金
- Centre National de la Recherche Scientifique-CNRS
- Institut National de la Sante et de la Recherche Medicale-INSERM
- Fondation pour la Recherche Medicale
- Conseil Regional d'Aquitaine
- Fondation ARC pour la Recherche sur le Cancer
- Ligue Contre le Cancer - Gironde
- SIRIC-BRIO
- Institut de Chimie des Substances Naturelles-ICSN
- Institut Europeen de Chimie et Biologie
- Universite Paris-Descartes
- Societe d'Acceleration de Transfert de Technologie d'Ile de France-SATT IDF-innov
- Institut Bergonie
- National Fund for Scientific Research of Belgium
- GIS-IBiSA
- Cellule Hotels a Projets of the Centre National de la Recherche Scientifique
The 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 anticancer 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 noncancer cells showed up to 100-fold less sensitivity to ICSN3250, in contrast to other mTOR inhibitors that did not show selectivity. Thus, our results define ICSN3250 as a new class of mTOR inhibitors that specifically targets cancer cells. Significance: ICSN3250 defines a new class of mTORC1 inhibitors that displaces phosphatidic acid at the FRB domain of mTOR, inducing cell death specifically in cancer cells but not in noncancer cells. (C) 2018 AACR.
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