Novel microtubule-targeting agents – the epothilones

Abstract

Epothilones are a new class of antimicrotubule agents currently in clinical trials. Their chemical structures are distinct from taxanes and are more amenable to synthetic modifi cation. Six epothilones have been studied in preclinical and clinical trials: patupilone (epothilone B), ixabepilone (BMS247550), BMS 310705, sagopilone (ZK-EPO), KOS-862 (epothilone D), and KOS-1584. In vitro data have shown increased potency in taxane-sensitive and taxane-resistant cancer cell lines. This enhanced cytotoxic effect has been attributed to epothilone being a poor substrate for p-glycoprotein drug resistance protein and having high affi nity to the various β tubulin isoforms. Phase I clinical data have shown different dose-limiting toxicities for each of the epothilones. These effects are drug specifi c, dose specifi c, and schedule of administration specifi c. While diarrhea and myelosuppression are the dose-limiting toxicities for patupilone and BMS 310705, respectively, neurologic toxicity, as seen with taxanes, is the dose-limiting toxicity of ixabepilone, sagopilone, and KOS-862. In an effort to decrease neurologic toxicity, investigators have modifi ed dosing schedules with limited success. Ixabepilone has the most mature clinical results with published phase II and III data, and regulatory approval for clinical use in the treatment of breast cancer. Ixabepilone has also been combined with other anticancer agents and has regulatory approval in combination with capecitabine for heavily treated breast cancer.

Epothilones Improve Axonal Growth and Motor Outcomes after Stroke in the Adult Mammalian CNS

“… 15 , 16 , 17 Interestingly, microtubule-stabilizing drugs have decreased acute injury after a CNS injury. 15 Intriguingly, in a spinal cord injury model, the systemic administration of epothilone B (EpoB), a blood-brain barrier-permeable microtubule-stabilizing drug approved by the US Food and Drug Administration (FDA) for the treatment of cancer, 18 increased regenerative axon outgrowth by microtubule polymerization and stabilization, reduced fibrotic scarring, and improved motor outcomes without obvious adverse effects. 17 …”

Enzymatic synthesis of epothilone A glycosides

“…Thus, epothilone A was selected for in vitro glycosylation in the current study because it has high demand in the cancer therapeutic development possessing high cytotoxic effects in taxane sensitive cell lines including P-glycoprotein overexpression (Cortes et al [ 2012 ]). Cytotoxic effects of epothilones with diverse human cancer cell line including lung cancer cell line (NCI-H460) (Kim et al [ 2003 ]), ovarian cancer cell line (SKOV-3) (Rogalska et al [ 2013 ]), breast cancer cell lines (Cheng et al [ 2008 ]), etc. have been reported in dose dependent manner.…”

“…Epothilones are a class of polypeptide macrolides produced by a few strains of myxo-bacterium such as Sorangium cellulosum (Cheng et al [ 2008 ]). Epothilones are structurally characterized as macrolactones with epoxy and keto-groups in a lactone ring and a side chain with a thiazole ring (Figure 1 ).…”

Anticancer Antibiotics

“…The discovery of epothilones goes back to 1987, when some strains of myxobacterium such as Sorangium cellulosum were found to produce these polyketide macrolide lactones, which possessed antifungal activity (Cheng et al 2008;Demain and Vaishnav 2011;Parajuli et al 2014). Epothilones seem to demonstrate similarities with taxanes in their mechanism of anti-tumor activity as well as their side effects (Fornier 2007).…”

“…Furthermore, ixabepilone (ixempra) has been approved for treatment of metastatic and locally advanced breast cancer (Zhang et al 2014). Unfortunately, neurologic toxicity has been associated with the use of ixabepilone (Cheng et al 2008) (Fig. 4.5).…”