Revisiting microtubule targeting agents: α-Tubulin and the pironetin binding site as unexplored targets for cancer therapeutics

Molecules that bind to tubulin and disrupt tubulin dynamics are known as microtubule targeting agents. Treatment with a microtubule targeting agent leads to cell cycle arrest followed by apoptosis. Tubulin inhibitors have been highly effective in the clinical treatment of a variety of tumors and are being investigated for treatment of several other diseases. Currently, all FDA approved microtubule inhibitors bind to beta-tubulin. Given the overall success of tubulin-binding agents in anticancer chemotherapy, alpha-tubulin is an attractive and unexplored target. Herein, we will discuss pironetin, the only compound known to bind alpha-tubulin, with particular focus on the known biological properties, the total syntheses, exploration of its structure-activity relationship, and future directions.