Discovery of Novel Microtubule Inhibitors as Potential Anticancer Drugs

Abstract

Tubulin, the major protein compound of microtubules, is the target of numerous antimitotic agents. Antimitotic agents have been used clinically to treat patients with neoplastic disease, a major drawback is the loss of efficacy over time because of the development of resistance due to express MDR protein. There is a need for new compounds that are effective in treating drug-resistant tumors. This review article focuses on recent research in our laboratory on the development of novel microtubules inhibitors. Three anti-tubulin compounds, including natural product (Salvinal) and synthetic chemicals (BPR0Y007 and BPR0L075), with potent anti-cancer property, were obtained by high-throughput screening or rational drug design based primarily on in vitro tubulin polymerization and the inhibition of cell proliferation assay. First, Salvinal, a compound isolated from Salvia miltiorrhizae Bunge (Dansen), possesses anti-proliferative activity against various human cancer cells. It is a novel type of microtubule inhibitor against cancer cell growth through mitotic arresting and apoptotic induction. Secondly, BPR0Y007, which is a dual inhibitor of both tubulin and topoisomerase 1 and can induce a rapid caspase activation involving upregulation of Fas (CD95/APO-1) and wild-type p53. Finally, BPR0L075, a novel synthetic indole compound designed from CA-4, is efficacious in suppressing cell growth in a variety of solid tumor models and exhibits significant antitumoral efficacy in vivo. BPR0L075 causes cell cycle arresting in G2/M phase and induces apoptosis that is associated with change in Bcl-2, cyclin Bi, Cdc2 and Cdc25C. These compounds are all poor substrates for transport by Pgp170/MDR and MRP. Thus, they have potential for management of various malignancies, particularly for patients with demonstrated drug resistance. BPR0L075 is now planning to enter the phase I clinical trial, is a current highlight of our drug development program.