Structural Modification of the 3,4,5-Trimethoxyphenyl Moiety in the Tubulin Inhibitor VERU-111 Leads to Improved Antiproliferative Activities

Colchicine binding
site inhibitors (CBSIs) hold great potential
in developing new generations of antimitotic drugs. Unlike existing
tubulin inhibitors such as paclitaxel, they are generally much less
susceptible to resistance caused by the overexpression of drug efflux
pumps. The 3,4,5-trimethoxyphenyl (TMP) moiety is a critical component
present in many CBSIs, playing an important role in maintaining suitable
molecular conformations of CBSIs and contributing to their high binding
affinities to tubulin. Previously reported modifications to the TMP
moiety in a variety of scaffolds of CBSIs have usually resulted in
reduced antiproliferative potency. We previously reported a potent
CBSI, VERU-111, that also contains the TMP moiety. Herein, we report
the discovery of a VERU-111 analogue 13f that is significantly
more potent than VERU-111. The X-ray crystal structure of 13f in complex with tubulin confirms its direct binding to the colchicine
site. In addition, 13f exhibited a strong inhibitory
effect on tumor growth in vivo.