Flavaglines are a family of anticancer natural products that relieve the resistance to cancer chemotherapies and display a strong cytotoxicity that is specific to cancer cells. We identified the first synthetic flavaglines that inhibit cell proliferation and viability (IC50~1 nM) at lower doses than did the parent natural compounds. These synthetic flavaglines retain their potency against multiresistant cell lines, induce apoptosis independently of �classical� apoptosis pathways and potentiates the effects of chemotherapeutic agents.Not only flavaglines are not toxic to non-cancer cells, but they protect normal cells from various stresses. Thus, we demonstrated for the first time that these compounds protect the heart and neurons from the adverse effects of cancer chemotherapies involving anthracyclines and cisplatin.An extensive SAR study, which led to the discovery of original derivatives with enhanced pharmacological properties, will be also presented.A ligand for affinity chromatography was designed and synthesized based on this SAR information, and used for the identification of prohibitins-1 and -2 as the molecular targets.Prohibitin-1 (PHB1) and its homologue prohibitin-2 (PHB2) are pleiotropic proteins that act as a hub for many signaling pathways to regulate metabolism, cell migration, division and survival. We demonstrated that the binding of flavaglines to PHBs prevents interaction between PHBs and CRaf and, thereby, inhibits CRaf activation and subsequently CRaf-MEK-ERK signaling, which is critical to survival and proliferation of cancer cells.We will present the SAR, in vivo activity, and the identification and validation of PHBs as the molecular target for flavaglines.

SAR, identification of the molecular targets and therapeutic potential of original anticancer natural products: Flavaglines

245th National Meeting (2013)

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