6X1C

Tubulin-RB3_SLD-TTL in complex with compound 5j

6X1C の概要

• エントリーDOI: 10.2210/pdb6x1c/pdb
• 分子名称: Tubulin alpha-1B chain, 4-(2-chlorofuro[3,2-d]pyrimidin-4-yl)-7-methoxy-3,4-dihydroquinoxalin-2(1H)-one, PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER, ... (12 entities in total)
• 機能のキーワード: microtubule inhibitor, colchicine, cell cycle, cancer, cell cycle-inhibitor complex, cell cycle/inhibitor
• 由来する生物種: Rattus norvegicus (Rat); 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 265076.53

構造登録者

White, S.W.,Yun, M. (登録日: 2020-05-18, 公開日: 2021-09-22, 最終更新日: 2023-10-18)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.9 Å)