Agents Targeting Microtubules and Mitotic Processes

Abstract

Overview The treatment of many diseases owes much to the importance of medicines derived from natural sources, and the treatment of malignant disease is no exception. Billions of years of evolutionary pressure have resulted in the natural selection of plants, fungi, and microorganisms capable of producing potent and specific toxins. After several plant‐derived compounds and other natural products, many of which targeted the mitotic processes, demonstrated prominent anticancer activity in the 1950s and 1960s, the microtubule was recognized as a subcellular target of major strategic importance. The first widely used class of antimicrotubule agents, the plant‐derived vinca alkaloids, had been the mainstay of both palliative and curative regimens for treating malignancies for several decades. The addition of the plant‐derived taxanes, which possess a unique mechanism of action and anticancer spectra, to our therapeutic arsenal several decades later resulted in renewed interest in the microtubule and mitotic processes as targets for which to develop cancer therapeutics, as well as in the identification of other natural products to treat cancers. More recently, several plant‐ and marine‐derived compounds as well as synthetic agents with yet even more distinctive disruptive actions on microtubules and other mitotic constituents have been identified. These include the analogs of the epothilones and halichondrin B, which were isolated from soil‐dwelling myxobacterium and marine sponges, respectively. They also include potent antimicrotubule agents, such as analogs of maytansine and dolastatin, which are components of antibody‐drug conjugates. This chapter focuses on the microtubule as a target for therapeutic development and antimicrotubule agents that comprise our therapeutic armamentarium.