Discovery and development of eribulin, a macrocyclic ketone analog of halichondrin B, for treatment of advanced breast cancer

Marine natural products represent rich sources of novel compounds for drug discovery. Owing to their roles in chemical defense, marine natural products are often remarkably potent in order to overcome highly diluting ocean environments. Halichondrin B (HB), originally isolated from the sponge Halichondria okadai, is one such compound. Early reports of HB's remarkable antitumor activity led to significant interest in developing it as a new anticancer drug, but limited natural supplies ultimately foiled such efforts. Fortunately, the total synthesis of HB plus the discovery that its anticancer activity resided in its macrolactone “right half” moiety provided an opportunity to develop structurally simplified, fully synthetic analogs. Eribulin, a synthetic analog of HB's right half, retains HB's high potency with low/sub-nM activity against human cancer cells in vitro. Mechanistically, eribulin is a novel microtubule dynamics inhibitor that disrupts mitotic spindle formation, causing apoptosis after 10 – 12 hours of irreversible mitotic blockade. In vivo, eribulin induces tumor regression and long-term survival of nude mice bearing human tumor xenografts. Eribulin (as Halaven®) is now approved for clinical use in the United States, European Union, Japan and many other countries for treatment of certain patients with advanced breast cancer.