posted on 2022-12-13, 14:08authored bySongwen Lin, Tingting Du, Jingbo Zhang, Deyu Wu, Hua Tian, Kehui Zhang, Lin Jiang, Duo Lu, Li Sheng, Yan Li, Ming Ji, Xiaoguang Chen, Heng Xu
Targeting
the colchicine binding site on tubulin is a promising
strategy to develop cancer therapeutics. Herein, we describe our systematic
structure–activity relationship studies of benzamide derivatives
that lead to an identification of a potent and orally active tubulin
inhibitor 48, which occupied all three zones of the colchicine
binding site in the X-ray co-crystal structure, inhibited tubulin
polymerization, promoted mitotic blockade and apoptosis, and exhibited
significant antiproliferative activities against various cancer cell
lines. Compound 48 demonstrated favorable pharmacokinetic
profiles, robust in vivo antitumor efficacies, and
acceptable safety profiles. Furthermore, 48 overcame
drug resistance in the paclitaxel-resistant A549 xenograft model.
Collectively, 48 has been advanced into further preclinical
evaluation for the development of next-generation microtubule-targeting
drugs.