5440 The epothilones comprise a novel class of non-taxane, natural microtubule stabilizing macrolides produced by the cellulose-degrading myxobacteria strain Sorrangium cellulosum. ABJ879 is a semi-synthetic derivative of the bacterially produced epothilone B that has been selected from several hundred analogs produced in an extensive medicinal chemistry effort. ABJ879 was found to induce tubulin polymerization in vitro slightly more potently than paclitaxel. At the cellular level, however, ABJ879 proved to be markedly more potent than paclitaxel. Thus, the average IC50s of ABJ879 and paclitaxel on a panel of non-multi-drug resistant (MDR) cell lines were 0.09 nM and 4.7 nM, respectively. Importantly, in contrast to paclitaxel, ABJ879 retained full activity against cancer cells overexpressing the drug efflux pump P-gp (mdr-1 gene product) or harboring tubulin mutations. Assessment of the in vitro drug exposure dependence further demonstrated that ABJ879 attains its full anti-proliferative potential at much shorter incubation times than paclitaxel. In experimental human tumor xenograft models in nude mice, ABJ879 was demonstrated to be a potent antitumor agent. ABJ879 was capable of producing transient regressions and inhibition of tumor growth in slow-growing NCI H-596 lung adenocarcinoma tumors and HT-29 colon tumors, and inhibition of tumor growth in fast growing, difficult-to-treat NCI H-460 large cell lung tumors. Importantly, single administration of ABJ879 was capable of inducing long-lasting regressions and cures in Taxol®-resistant KB-8511 epidermoid carcinomas. Extended dosing using schedules permitting body weight recovery prior to the next administration appeared to afford improved antitumor effects.In summary, ABJ879 thus represents a novel epothilone analog that in preclinical cancer model systems proves to be markedly more potent than paclitaxel, and is able to successfully overcome several of the known paclitaxel-resistance mechanisms. Based on this promising pre-clinical profile, ABJ879 has been selected for Novartis-sponsored Phase I clinical trials.