p.2 of proposal)This is a revised phase II application concerned with developing a method of production of epithilone D. Epothilones are polyketides isolated from the myxobacterium Sorangium cellulosum that have shown great promise as anticancer agents. Although the two compound classes are structurally unrelated, the mechanism of action, stabilization of microtubules, is similar to that of paclitaxel (Taxol). Epithilones are active against Taxol resistant cell lines, are effective against multiple drug resistant cell lines, and are more water-soluble and thus more easily administered than Taxol. Because of these properties, one epithilone, epithilone D, has been chemically synthesized, and is being considered for clinical evaluation. Yields are low, both in the chemical synthesis and in the natural host organism. In phase I the epithilone biosynthesis genes were cloned and sequenced, and expressed in the fast growing heterologous host Streptomyces coelicor. A problem was that expression of epithilone biosynthesis genes was toxic to this host. Phase 2 work seeks to first overcome or circumvent this toxicity. Following this, a series of steps will be taken to maximize biosynthesis of Epithilone D.
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