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
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.