Study of a Potent Small‐Molecule Benzosuberene Anti‐Cancer Agent

Abstract

The discovery of a benzosuberene‐based, small‐molecule anti‐cancer agent (KGP18) with remarkable cytotoxicity against selected human cancer cell lines (BMC 2008 16, 8161–8171) provided the inspiration for a collaborative research program to investigate the mechanism of action of this compound and related benzosuberene analogues. The structure of KGP18 and its ability to inhibit tubulin polymerization into microtubules in vitro suggests that it may act as a vascular disrupting agent (VDA). An adequate blood supply is required for tumor growth and metastasis. VDAs represent a promising new class of anti‐cancer agents that function by selectively disrupting the tumor vasculature, thus starving the tumor of nutrients and oxygen via an adequate blood supply. Tubulin‐binding VDAs inhibit microtubule assembly in the activated endothelial cells, lining the tumor vasculature, leading to cytoskeletal reorganization, activation of RhoA and RhoA kinase, increased vascular permeability, cell rounding and detachment, and vessel occlusion. The lead benzosuberene analogue (KGP18) binds to tubulin at the colchicine binding site as determined by a competitive radiometric assay. Flow cytometry indicates that MDA‐MB‐231 cells treated with KGP18 are arrested at the G2/M phase of the cell cycle. (Supported by Oxigene Inc., the NIH, and CPRIT).