7LZ7

Tubulin-RB3_SLD-TTL in complex with compound 5k

Summary for 7LZ7

• Entry DOI: 10.2210/pdb7lz7/pdb
• Descriptor: Tubulin alpha-1B chain, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER, ... (12 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: 6
• Total formula weight: 265065.73

Authors

White, S.W.,Yun, M. (deposition date: 2021-03-09, release date: 2021-09-22, Last modification date: 2023-10-18)

Primary citation

Banerjee, S.,Mahmud, F.,Deng, S.,Ma, L.,Yun, M.K.,Fakayode, S.O.,Arnst, K.E.,Yang, L.,Chen, H.,Wu, Z.,Lukka, P.B.,Parmar, K.,Meibohm, B.,White, S.W.,Wang, Y.,Li, W.,Miller, D.D.
X-ray Crystallography-Guided Design, Antitumor Efficacy, and QSAR Analysis of Metabolically Stable Cyclopenta-Pyrimidinyl Dihydroquinoxalinone as a Potent Tubulin Polymerization Inhibitor.
J.Med.Chem., 64:13072-13095, 2021

PubMed Abstract: Small molecules that interact with the colchicine binding site in tubulin have demonstrated therapeutic efficacy in treating cancers. We report the design, syntheses, and antitumor efficacies of new analogues of pyridopyrimidine and hydroquinoxalinone compounds with improved drug-like characteristics. Eight analogues, , , , , , , , and , showed significant improvement in metabolic stability and demonstrated strong antiproliferative potency in a panel of human cancer cell lines, including melanoma, lung cancer, and breast cancer. We report crystal structures of tubulin in complex with five representative compounds, , , , , and , providing direct confirmation for their binding to the colchicine site in tubulin. A quantitative structure-activity relationship analysis of the synthesized analogues showed strong ability to predict potency. , (4 mg/kg) and (5 mg/kg) significantly inhibited tumor growth as well as melanoma spontaneous metastasis into the lung and liver against a highly paclitaxel-resistant A375/TxR xenograft model.

PubMed: 34406768
DOI: 10.1021/acs.jmedchem.1c01202

Experimental method

X-RAY DIFFRACTION (2.8 Å)