6N47

The structure of SB-2-204-tubulin complex

Summary for 6N47

• Entry DOI: 10.2210/pdb6n47/pdb
• Descriptor: Tubulin alpha-1B chain, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, 4-(2-chloropyrido[3,2-d]pyrimidin-4-yl)-7-methoxy-3,4-dihydroquinoxalin-2(1H)-one, ... (13 entities in total)
• Functional Keywords: tubulin, complex, inhibitor, structural protein
• Biological source: Sus scrofa (Pig); More
• Total number of polymer chains: 6
• Total formula weight: 265189.89

Authors

Arnst, K.,Banerjee, S.,Wang, Y.,Li, W.,Miller, D.,Li, W. (deposition date: 2018-11-17, release date: 2019-11-13, Last modification date: 2024-03-13)

Primary citation

Arnst, K.E.,Banerjee, S.,Wang, Y.,Chen, H.,Li, Y.,Yang, L.,Li, W.,Miller, D.D.,Li, W.
X-ray Crystal Structure Guided Discovery and Antitumor Efficacy of Dihydroquinoxalinone as Potent Tubulin Polymerization Inhibitors.
Acs Chem.Biol., 14:2810-2821, 2019

PubMed Abstract: Because of its multifaceted role in cellular functions, tubulin is a validated and productive drug target for cancer therapy. While many tubulin inhibitors demonstrate clinical efficacy, they are often limited by the development of multidrug resistance. Therefore, implementation of tubulin inhibitors that can overcome resistance could provide significant therapeutic benefits. To optimize our previously reported tubulin inhibitor, , we designed and synthesized two new analogues, and , based on the crystal structure of in complex with tubulin protein. and achieved enhanced binding at the colchicine site in tubulin and also showed improved metabolic stability and antiproliferative potency . Functional studies confirmed that and inhibit tubulin polymerization, arrest cells in the G/M phase of the cell cycle, interfere with cancer cell migration and proliferation, and enhance apoptotic cascades. When evaluated , exhibited antitumor and vascular disrupting action against paclitaxel-resistant mouse xenograft models, strongly suggesting the potential of this scaffold to overcome multidrug resistance for cancer therapy.

PubMed: 31714738
DOI: 10.1021/acschembio.9b00696

Experimental method

X-RAY DIFFRACTION (2.6 Å)