Monday, July 30, 2007 - 8:00 AM

Unnatural selection and the evolution of anticancer agent Ixabepilone: Optimizing the fermentation and drug-like properties of epothilones

Gregory D. Vite, Oncology Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 4000, Princeton, NJ 08543-4000

The epothilones are isolated as secondary metabolites from fermentation of a soil myxobacterium, Sorangium cellulosum. These natural products are potent cytotoxic agents that exert their cell-killing effects via microtubule stabilization.  They are particularly attractive as drug leads owing to their unique ability to overcome multiple tumor-resistance mechanisms.  Among the epothilone natural products, Epothilone B has the most compelling in vitro properties.  However, preliminary work in these laboratories suggested that improvements in drug-like properties of the natural product were desirable.  Therefore, a semisynthesis campaign was initiated to prepare optimized epothilone analogs for clinical investigation.  Efficient fermentation of Epothilone B was necessary to provide adequate material for chemical derivatization.  Strain improvements and modifications to the original fermentation process enabled the recovery of Epothilone B as a major metabolite.  Combination of semisynthesis and microbial biotransformation was utilized in the lead optimization phase.  New epothilone analogs were evaluated for in vitro activity and metabolic stability.  Promising leads were evaluated in tumor models in athymic mice. Ixabepilone (BMS-247550), a novel lactam analog, emerged as a superior agent with broad spectrum efficacy against human tumor xenografts.  This robust preclinical activity was recapitulated in early human clinical trials for several cancers, including metastatic breast cancer and prostate cancer.   Currently, Ixabepilone is in late-stage (i.e., Phase III) clinical trials for metastatic breast cancer.