Epothilone (NSC 703147)

1999 Since the 1990s, fermentation products, such as epothilones, have been known to have anticancer activity. Studies showed epothilone B to be especially active. In 1999, Dr. Samuel Danishefsky, of Memorial Sloan-Kettering Cancer Center, submitted a RAID application for several epothilone analogs, including 12,13-desoxyepothilone B (dEpoB, NSC 703147), which had been shown to be much less toxic than epothilone B. DTP provided the first confirmation that epothilones worked through a microtubule-based mechanism of action and was the first to demonstrate that epothilones A and B interfere with the ability of paclitaxel to bind to tubulin. Further evaluation showed that cells that were resistant to multiple drugs, including paclitaxel, retained sensitivity to epothilones. In vivo studies of dEpoB showed that this analog was well tolerated and virtually curative against a variety of tumors in animal models, including some resistant to paclitaxel.

2001 KOSAN Biosciences obtained the license for dEpoB and began collaborating with DTP in March 2001. dEpoB was first tested in humans in October 2001. Phase II clinical trials are under way.

¹ Memorial Sloan-Kettering Cancer Center. Cytotoxic natural products: the epothilones.

² Lineberger Comprehensive Cancer Center, Jenny Ting Lab. Cancer/Pharmacology.

Link:

12,13-desoxyepothilone B poster (pdf)

“The whole epothilone story, which is by no means complete, is an important case history in demonstrating the close interactivity of complex, target-oriented chemical synthesis and drug discovery.”¹ Paclitaxel and dEpoB both belong to a class of chemotherapeutic agents that arrest the cell cycle by binding microtubules and preventing their dissociation.² However, dEpoB appears to succeed where paclitaxel fails.