New tubulin targeting agents currently in clinical development

Abstract

Background: The first tubulin targeting agents were approved as cancer chemotherapeutics over 40 years ago and tubulin as an antitumor target continues to attract significant drug discovery and development attention. Mechanism of action as defined by tubulin binding sites and effect on microtubules distinguishes these agents, but the end result is equivalent in that microtubule disruption leads to cell cycle arrest at G2/M phase of the cell cycle and subsequent apoptotic cell death. Objectives: The goal of this review is to describe the state of clinical development of tubulin targeting agents as of early 2008, with descriptions of clinical experience slanted toward the most advanced trials for each agent. Method: Objective information in this review was obtained exclusively from public sources that included journals, scientific meeting abstracts, posters and oral presentations, websites and public presentations from companies. Opinions expressed in this review are exclusively from the author. Results/conclusions: A large number of tubulin targeting agents are currently in clinical development, including microtubule stabilizing and destabilizing compounds acting through all three of the characterized tubulin binding sites. With the approval of ixabepilone for refractory breast cancer, the epothilones appear best positioned to make an impact among the new microtubule stabilizing compounds. There are 17 microtubule destabilizing agents under clinical assessment, with many only in Phase I and results to date include at best modest efficacy signals with no obvious indication trend.

Keywords::

• colchicine
• combretastatin
• epothilone
• MDR
• microtubule
• multi-drug resistance
• taxane
• tubulin
• vascular disruption
• vinca alkaloid