Epothilone analogs in clinical development

As indicated above, the first compound of the epothilone class of microtubule inhibitors to enter clinical trials was Epo B EPO906, Novartis vide supra). This involved initial testing in two phase I studies, employing either a weekly or a 

Phase II trials with BMS-247550 (1) have produced objective responses for a variety of tumor types, including tumors that had been refractory to treatment with platinum-based drugs or taxanes. Based on these highly promising results, the compound has been advanced to phase III studies, which are currently ongoing in parallel with several phase II trials (including combination studies).  

Phase I clinical studies have recently been completed with Epo D, and phase II trials with the compound are now ongoing together with an additional phase I smdy [sponsored by Kosan Biosciences (as KOS-862)]. As for BMS-247550, KOS-862 was demonstrated to induce microtubule bundling in patient PBMCs, and several tumor responses have been noted in the phase I studies.  

The most recent additions to the portfolio of epothilone-type clinical development compounds are the semisynthetic derivatives BMS-310705 (23), which differs from Epo B by the presence of a primary amino group at C21, and C20-desmethyl-C20-methylsulfanyl-Epo B (32, ABJ879). As indicated above, BMS-310705 (23) exhibits improved water-solubility over BMS-247550 (1), thus allowing the use of clinical formulations not containing Cremophor-EL. Accordingly, no hypersensitivity reactions were observed in phase I studies with BMS-310705 (23) in contrast to BMS-247550 (1) (in the absence of premedication). 

The author would like to thank all former coUahorators at Novartis for their help and inspiration over the last several years. In particular, I want to acknowledge the support hy Dr. A. Fldrsheimer, Dr. T. O Reilly, and Dr. M. Wartmann, who had worked with me on the epothilone program at Novartis since its very beginning. My sincere thanks also goes to Prof. K. C. Nicolaou and his group at the The Scripps Research Institute for a very productive collaboration. 

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Epothilone Analogs in Clinical Development and Related Stractures... 

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