Recent Developments in the Chemical Biology of Epothilones

Abstract

Epothilones A and B are naturally occurring microtubule-stabilizers, which inhibit the growth of human cancer cells in vitro at nM or even sub-nM concentrations. In contrast to paclitaxel (Taxol) epothilones are also active against different types of multidrug-resistant cancer cell lines in vitro and against multidrug-resistant tumors in vivo (epothilone B). Their attractive preclinical profile has made epothilones important lead structures in the search for improved cytotoxic anticancer drugs and epothilone B is currently undergoing phase II clinical trials. Numerous synthetic and semi-synthetic analogs have been prepared since the absolute stereochemistry of epothilone B was first disclosed in mid-1996 and their in vitro biological activity has been determined. Apart from generating a wealth of SAR information, these efforts have led to the identification of at least four compounds (in addition to epothilone B), which are currently at various stages of clinical evaluation in humans. This review is first intended to provide a summary of the basic features of the in vitro biological profile of epothilone B, with particular emphasis on recent developments in this area. A second part will outline the most relevant aspects of the epothilone SAR with regard to effects on tubulin polymerization, in vitro antiproliferative activity, and in vivo antitumor activity. This will include a brief discussion of research directed at the determination of the bioactive conformation of epothilones. In a final section, the preclinical profile of those epothilone analogs currently in clinical development will be discussed in greater detail.

Developing Therapeutic Approaches to Tau, Selected Kinases, and Related Neuronal Protein Targets

“…Improved taxanes have been synthesized that are not Pgp substrates (Cisternino et al 2003;Ballatore et al 2007a;Ojima et al 2008;Metzger-Filho et al 2009), but recent data from our laboratory suggest that such compounds still have poor brain penetration (Brunden et al 2011). However, several examples from the epothilone class of MT-stabilizing compounds, some of which have progressed to clinical testing for cancer (Altmann 2005;Beer et al 2007; Denduluri al. 2007), partition readily across the BBB and one of these molecules, epothilone D, has a long-lasting pharmacodynamic effect in the brain (Brunden et al 2011).…”

The Epothilones: New Therapeutic Agents for Castration-Resistant Prostate Cancer

“…These agents have also been shown to inhibit tumor growth in taxane-resistant cell lines, suggesting a lack of crossresistance between the two drug classes [27,30,36,37].…”

Novel microtubule-targeting agents – the epothilones

“…Hence, the epoxide ring is not a requirement for anticancer effect (Altmann 2005). A second generation …”