6NNG

Tubulin-RB3_SLD-TTL in complex with compound DJ95

6NNG の概要

• エントリーDOI: 10.2210/pdb6nng/pdb
• 分子名称: Tubulin alpha-1B chain, 2-(1H-indol-6-yl)-4-(3,4,5-trimethoxyphenyl)-1H-imidazo[4,5-c]pyridine, PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER, ... (12 entities in total)
• 機能のキーワード: microtubule inhibitor, colchicine, cancer, cell cycle
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 264791.21

構造登録者

Kumar, G.,Wang, Y.,Li, W.,White, S.W. (登録日: 2019-01-15, 公開日: 2019-07-10, 最終更新日: 2024-12-25)

主引用文献

Arnst, K.E.,Wang, Y.,Lei, Z.N.,Hwang, D.J.,Kumar, G.,Ma, D.,Parke, D.N.,Chen, Q.,Yang, J.,White, S.W.,Seagroves, T.N.,Chen, Z.S.,Miller, D.D.,Li, W.
Colchicine Binding Site Agent DJ95 Overcomes Drug Resistance and Exhibits Antitumor Efficacy.
Mol.Pharmacol., 96:73-89, 2019

PubMed Abstract: Interfering with microtubule dynamics is a well-established strategy in cancer treatment; however, many microtubule-targeting agents are associated with drug resistance and adverse effects. Substantial evidence points to ATP-binding cassette (ABC) transporters as critical players in the development of resistance. Herein, we demonstrate the efficacy of DJ95 (2-(1-indol-6-yl)-4-(3,4,5-trimethoxyphenyl)-1-imidazo[4,5-]pyridine), a novel tubulin inhibitor, in a variety of cancer cell lines, including malignant melanomas, drug-selected resistant cell lines, specific ABC transporter-overexpressing cell lines, and the National Cancer Institute 60 cell line panel. DJ95 treatment inhibited cancer cell migration, caused morphologic changes to the microtubule network foundation, and severely disrupted mitotic spindle formation of mitotic cells. The high-resolution crystal structure of DJ95 in complex with tubulin protein and the detailed molecular interactions confirmed its direct binding to the colchicine site. In vitro pharmacological screening of DJ95 using SafetyScreen44 (Eurofins Cerep-Panlabs) revealed no significant off-target interactions, and pharmacokinetic analysis showed that DJ95 was maintained at therapeutically relevant plasma concentrations for up to 24 hours in mice. In an A375 xenograft model in nude mice, DJ95 inhibited tumor growth and disrupted tumor vasculature in xenograft tumors. These results demonstrate that DJ95 is potent against a variety of cell lines, demonstrated greater potency to ABC transporter-overexpressing cell lines than existing tubulin inhibitors, directly targets the colchicine binding domain, exhibits significant antitumor efficacy, and demonstrates vascular-disrupting properties. Collectively, these data suggest that DJ95 has great potential as a cancer therapeutic, particularly for multidrug resistance phenotypes, and warrants further development. SIGNIFICANCE STATEMENT: Paclitaxel is a widely used tubulin inhibitor for cancer therapy, but its clinical efficacy is often limited by the development of multidrug resistance. In this study, we reported the preclinical characterization of a new tubulin inhibitor DJ95, and demonstrated its abilities to overcome paclitaxel resistance, disrupt tumor vasculature, and exhibit significant antitumor efficacy.

PubMed: 31043459
DOI: 10.1124/mol.118.114801

実験手法

X-RAY DIFFRACTION (2.397 Å)