7CBZ

Crystal structure of T2R-TTL-A31 complex

7CBZ の概要

• エントリーDOI: 10.2210/pdb7cbz/pdb
• 分子名称: Tubulin alpha-1B chain, GUANOSINE-5'-DIPHOSPHATE, Tubulin beta chain, ... (11 entities in total)
• 機能のキーワード: tubulin, cancer, cell cycle-inhibitor complex, cell cycle/inhibitor
• 由来する生物種: Sus scrofa (Pig); 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 270289.60

構造登録者

Yang, J.H.,Yan, W. (登録日: 2020-06-15, 公開日: 2021-06-23, 最終更新日: 2023-11-29)

主引用文献

Wang, L.,Zheng, Y.,Li, D.,Yang, J.,Lei, L.,Yan, W.,Zheng, W.,Tang, M.,Shi, M.,Zhang, R.,Cai, X.,Ni, H.,Ma, X.,Li, N.,Hong, F.,Ye, H.,Chen, L.
Design, Synthesis, and Bioactivity Evaluation of Dual-Target Inhibitors of Tubulin and Src Kinase Guided by Crystal Structure.
J.Med.Chem., 64:8127-8141, 2021

PubMed Abstract: Klisyri (KX01) is a dual tubulin/Src protein inhibitor that has shown potential therapeutic effects in several tumor models. However, a phase II clinical trial in patients with bone-metastatic castration-resistant prostate cancer was halted because of lack of efficacy. We previously reported that KX01 binds to the colchicine site of β-tubulin and its morpholine group lies close to α-tubulin's surface. Thus, we hypothesized that enhancing the interaction of KX01 with α-tubulin could increase tubulin inhibition and synthesized a series of KX01 derivatives directed by docking studies. Among these derivatives, exhibited more than 10-fold antiproliferation activity in several tumor cells than KX01 and significantly improved antitumor effects. The X-ray crystal structure suggested that both bound to the colchicine site and extended into the interior of α-tubulin to form potent interactions, presenting a novel binding mode. A potential clinical candidate for cancer therapy was identified in this study.

PubMed: 34081857
DOI: 10.1021/acs.jmedchem.0c01961

実験手法

X-RAY DIFFRACTION (2.61 Å)