Preclinical pharmacological profile of ABJ879, a novel epothilone B analog with potent and protracted anti-tumor activity

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