Epothilone clinical trials with

From a totally synthetic aspect, another group has introduced a very interesting molecule that is now in Phase II clinical trials with Schering AG. This is the molecule known as ZK-EPO (Figure 8.11), which for a number of years did not have a published structure. In 2006, the full rationale for and synthetic methods employed were pubhshed for this molecule, which is a modification of epothilone B with a benzothiazole in place of the thiazole on the Western side (effectively a ring-closure of the pendant thiazole in epothilone B), and the substitution of an allyl group for the methyl on the Eastern side of epothilone B. Although these... 

For a review on clinical trials with epothilones see H. M. Coley, Cancer Treat. Rev., 2008, 34, 378. 

BMS-247550 (INN Ixabepilone) (34c) is a semisynthetic analogue of Epothilone B developed by Bristol-Myers Squibb currently in phase II/IH clinical trials. Like Epothilone B, BMS-247550 is a stabilising tubulin antagonist with broad anti-tumour activity [115].The drug is active towards Taxol sensitive and insensitive cell lines, including A2780Tax ovarian carcinoma cells with defined B-tubulin mutations (F — V or... 

Roch6 H, Yelle L, Cognetti F, Mauriac L, Bunnell C, Sparano J, Kerbrat P, Delord JP, Vahdat L, Peck R, Lebwohl D, Ezzeddine R, Cur6 H. Phase II clinical trial of ixabepilone (BMS-247550), an epothilone B analog, as first-line therapy in patients with metastatic breast cancer previously treated with anthracycline chemotherapy. J Clin Oncol 2007 25(23) 3415-20. 

An epothilone analog with an isoxazole-bearing side chain has recently entered Phase I clinical trials this compound (iso-fludelone (52)) will be discussed in Section 3.3.3.3. 

At this point in time, nine epothilone-derived structures are known to have been advanced to clinical trials in humans one of these, ixabepilone, has received FDA approval in 2007, which has provided final validation of the lead potential of epothilones for anticancer drug discoveiy. On the other hand, and with the exception of UTDl and iso-fludelone, the development of all other candidate drugs in cancer is either uncertain (patupilone, sagopi-lone) or seems to have been terminated. However, Epo D is now in clinical trials for neurodegenerative diseases. Clearly, there are still numerous interesting preclinical candidates to be explored further, but it remains to be seen whether any of these will be taken into the clinic (either in cancer, or, perhaps, for neurodegenerative diseases) and, if so, whether any can be developed into a clinical drug. 

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