6O5N

Tubulin-RB3_SLD-TTL in complex with compound 10ab

Summary for 6O5N

• Entry DOI: 10.2210/pdb6o5n/pdb
• Related: 6O5M
• Descriptor: Tubulin alpha-1B chain, [2-(4-methyl-1H-indol-3-yl)-1H-imidazol-5-yl](3,4,5-trimethoxyphenyl)methanone, Tubulin beta-2B chain, ... (11 entities in total)
• Functional Keywords: microtubule inhibitor, colchicine, cancer, cell cycle
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 6
• Total formula weight: 264564.13

Authors

Kumar, G.,Wang, Y.,Li, W.,White, S.W. (deposition date: 2019-03-04, release date: 2019-07-10, Last modification date: 2024-03-13)

Primary citation

Wang, Q.,Arnst, K.E.,Wang, Y.,Kumar, G.,Ma, D.,White, S.W.,Miller, D.D.,Li, W.,Li, W.
Structure-Guided Design, Synthesis, and Biological Evaluation of (2-(1H-Indol-3-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl) Methanone (ABI-231) Analogues Targeting the Colchicine Binding Site in Tubulin.
J.Med.Chem., 62:6734-6750, 2019

PubMed Abstract: ABI-231 is a potent, orally bioavailable tubulin inhibitor that interacts with the colchicine binding site and is currently undergoing clinical trials for prostate cancer. Guided by the crystal structure of ABI-231 in complex with tubulin, we performed structure-activity relationship studies around the 3-indole moiety that led to the discovery of several potent ABI-231 analogues, most notably and . The crystal structures of and in complex with tubulin confirmed their improved molecular interactions to the colchicine site. In vitro, biological studies showed that new ABI-231 analogues disrupt tubulin polymerization, promote microtubule fragmentation, and inhibit cancer cell migration. In vivo, analogue not only significantly inhibits primary tumor growth and decreases tumor metastasis in melanoma xenograft models but also shows a significant ability to overcome paclitaxel resistance in a taxane-resistant PC-3/TxR model. In addition, pharmacological screening suggested that has a low risk of potential off-target function.

PubMed: 31251599
DOI: 10.1021/acs.jmedchem.9b00706

Experimental method

X-RAY DIFFRACTION (3.003 Å)