Eleutherobin

Eleutherobin is the prototypical member of the eleutherobin class of tubulin inhibitors, consisting of 7 unique agents each isolated from several species of marine sponges. Its structure is well defined by NMR and the active enantiomer of the compound (based heavily on the orientation of the carbohydrate R-group motif) has been described. A synthetic pathway for its synthesis is published and freely available. Utilising direct binding experiments for tubulin stabilisation in a variety of approaches including reactions in free solution and in cellular models, eleutherobin demonstrates strong binding to tubulin which is consistently 5-10 fold less potent than the commonly utilised taxol, paclitaxel. Direct binding of eleutherobin to tubulin has been confirmed and it directly competes with paclitaxel for binding, suggesting that these drugs share a common binding site and mechanism. The inhibitory dose 50 (IC50) anti-prolferaitve range for this drug in multiple cancer cell lines is approximately10-140 nM. Use of a low concentration (50nM) of eleutherobin in cellular models induces microtubule stabilisation, cell cycle arrest at the G2/M phase and phenotypic nuclear morphology changes associated with mitotic catastrophe and mitotic slippage. Eleutherobin is also a substrate for the drug efflux pump, P-glycoprotein, which must be taken into account when selecting the cellular model to test the drug in. Additionally, eleutherobin can still bind and stabilise tubulin mutants which predispose to paclitaxel resistance which highlights the usefulness of eleutherobin in acting as an alternative tubulin probe in the context of this genetic background. Elutherobin is, therefore, a potent probe of tubulin biology in cellular models, including those bearing paclitaxel-nullifying tubulin mutations. Although SAR has been performed, the precise mode of binding to tubulin is not defined. Moreover, the potential for incidental ‘off targets’ with relevance to cell biology is incompletely mapped. Commercial supply of elutherobin is limited, with no vendors currently listed to purchase the drug, limiting its wider spread use as a commonly utilised probe.   

Even if the direct activity of eleutherobin on tubulin has been demonstrated in vitro, some structural components are potentially reactive (such as the Michael acceptor) and reversible and/or irreversible interactions with other targets may contribute to its activity in cells.