6XER

Tubulin-RB3_SLD in complex with colchicine

Summary for 6XER

• Entry DOI: 10.2210/pdb6xer/pdb
• Descriptor: Tubulin alpha-1B chain, Tubulin beta chain, Stathmin-4, ... (9 entities in total)
• Functional Keywords: microtubule inhibitor, colchicine, cell cycle, cancer, cell cycle-inhibitor complex, cell cycle/inhibitor
• Biological source: Rattus norvegicus (Rat); More
• Total number of polymer chains: 5
• Total formula weight: 214857.09

Authors

White, S.W.,Yun, M. (deposition date: 2020-06-13, release date: 2021-08-25, Last modification date: 2023-10-18)

Primary citation

Chen, H.,Deng, S.,Albadari, N.,Yun, M.K.,Zhang, S.,Li, Y.,Ma, D.,Parke, D.N.,Yang, L.,Seagroves, T.N.,White, S.W.,Miller, D.D.,Li, W.
Design, Synthesis, and Biological Evaluation of Stable Colchicine-Binding Site Tubulin Inhibitors 6-Aryl-2-benzoyl-pyridines as Potential Anticancer Agents.
J.Med.Chem., 64:12049-12074, 2021

PubMed Abstract: We previously reported a potent tubulin inhibitor CH-2-77. In this study, we optimized the structure of CH-2-77 by blocking metabolically labile sites and synthesized a series of CH-2-77 analogues. Two compounds, and , preserved the potency while improving the metabolic stability over CH-2-77 by 3- to 4-fold (46.8 and 29.4 vs 10.8 min in human microsomes). We determined the high-resolution X-ray crystal structures of (resolution 2.3 Å) and (resolution 2.6 Å) in complex with tubulin and confirmed their direct binding at the colchicine-binding site. , maintained its mode of action by inhibiting tubulin polymerization and was effective against P-glycoprotein-mediated multiple drug resistance and taxol resistance. , exhibited a strong inhibitory effect on tumor growth and metastasis in a taxol-resistant A375/TxR xenograft model without obvious toxicity. Collectively, this work showed that is a promising lead compound for further development as a potential anticancer agent.

PubMed: 34378386
DOI: 10.1021/acs.jmedchem.1c00715

Experimental method

X-RAY DIFFRACTION (2.5 Å)