Epothilones and their analogues -: a new class of promising microtubule inhibitors

Epothilones A and B are naturally occurring microtubule depolymerisation inhibitors, which inhibit the growth of human cancer cells in vitro at nanomolar or even sub-nanomolar concentrations. In contrast to paclitaxel (Taxol (R), Bristol-Myers Squibb) epothilones are also active against multi-drug resistant cancer cell lines and epothilone B exhibits potent in vivo antitumour activity against multidrug-resistant tumours In addition, epothilones A and & have been shown to be active in vitro against cell lines whose paclitaxel-resistance is derived from specific tubulin mutations. Their attractive preclinical profile has made epothilones important lead structures in the search for improved cytotoxic anticancer drugs and hundreds of analogues and derivatives of epothilones have been prepared and biologically characterised over the past four years. While chemical modifications have been reported for almost every position of the epothilone structural framework, the major focus has been on modifications of the epoxide moiety at C-12/C-13, the C-6-position, the ester linkage and the unsaturated heterocyclic side-chain. Several of the compounds thus produced exhibit low nM IC50 values for the inhibition of human cancer cell proliferation and may represent potential development candidates. Currently, two compounds, natural epothilone B and BMS247550, the lactam analogue of epothilone B, are undergoing clinical trials. An additional analogue, epothilone D, also known as deoxyepothilone B, appears to be in late stage preclinical development and may enter clinical trials in the near future.