7YHN

ANTI-TUMOR AGENT Y48 IN COMPLEX WITH TUBULIN

Summary for 7YHN

• Entry DOI: 10.2210/pdb7yhn/pdb
• Related: 6LS4
• Descriptor: Tubulin alpha-1B chain, Tubulin beta chain, Stathmin, ... (9 entities in total)
• Functional Keywords: mitosis, antitumor protein, structural protein
• Biological source: Sus scrofa (pig); More
• Total number of polymer chains: 5
• Total formula weight: 221641.89

Authors

Du, T.,Ji, M.,Hou, Z.,Lin, S.,Zhang, J.,Wu, D.,Zhang, K.,Lu, D.,Xu, H.,Chen, X. (deposition date: 2022-07-14, release date: 2023-07-26, Last modification date: 2024-02-07)

Primary citation

Lin, S.,Du, T.,Zhang, J.,Wu, D.,Tian, H.,Zhang, K.,Jiang, L.,Lu, D.,Sheng, L.,Li, Y.,Ji, M.,Chen, X.,Xu, H.
Optimization of Benzamide Derivatives as Potent and Orally Active Tubulin Inhibitors Targeting the Colchicine Binding Site.
J.Med.Chem., 65:16372-16391, 2022

PubMed Abstract: 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 , 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 demonstrated favorable pharmacokinetic profiles, robust antitumor efficacies, and acceptable safety profiles. Furthermore, overcame drug resistance in the paclitaxel-resistant A549 xenograft model. Collectively, has been advanced into further preclinical evaluation for the development of next-generation microtubule-targeting drugs.

PubMed: 36511661
DOI: 10.1021/acs.jmedchem.2c01208

Experimental method

X-RAY DIFFRACTION (2.6 Å)