6KRO

Tankyrase-2 in complex with RK-582

6KRO の概要

• エントリーDOI: 10.2210/pdb6kro/pdb
• 分子名称: Tankyrase-2, 6-[(2S,6R)-2,6-dimethylmorpholin-4-yl]-4-fluoranyl-1-methyl-1'-(8-methyl-4-oxidanylidene-3,5,6,7-tetrahydropyrido[2,3-d]pyrimidin-2-yl)spiro[indole-3,4'-piperidine]-2-one, ZINC ION, ... (7 entities in total)
• 機能のキーワード: tankyrase, parp, adp-ribosylation, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 25369.83

構造登録者

Niwa, H.,Shirai, F.,Sato, S.,Tsumura, T.,Okue, M.,Shirouzu, M.,Seimiya, H.,Umehara, T. (登録日: 2019-08-22, 公開日: 2020-04-01, 最終更新日: 2024-03-27)

主引用文献

Shirai, F.,Mizutani, A.,Yashiroda, Y.,Tsumura, T.,Kano, Y.,Muramatsu, Y.,Chikada, T.,Yuki, H.,Niwa, H.,Sato, S.,Washizuka, K.,Koda, Y.,Mazaki, Y.,Jang, M.K.,Yoshida, H.,Nagamori, A.,Okue, M.,Watanabe, T.,Kitamura, K.,Shitara, E.,Honma, T.,Umehara, T.,Shirouzu, M.,Fukami, T.,Seimiya, H.,Yoshida, M.,Koyama, H.
Design and Discovery of an Orally Efficacious Spiroindolinone-Based Tankyrase Inhibitor for the Treatment of Colon Cancer.
J.Med.Chem., 63:4183-4204, 2020

PubMed Abstract: Tankyrases (TNKS/TNKS2) belong to the poly(ADP-ribose) polymerase family. Inhibition of their enzymatic activities attenuates the Wnt/β-catenin signaling, which plays an important role in cancer pathogenesis. We previously reported the discovery of RK-287107, a spiroindoline-based, highly selective, potent tankyrase inhibitor. Herein we describe the optimization process of RK-287107 leading to RK-582, which exhibits a markedly improved robust tumor growth inhibition in a COLO-320DM mouse xenograft model when orally administered. In addition to the dose-dependent elevation and attenuation of the levels of biomarkers AXIN2 and β-catenin, respectively, results of the TCF reporter and cell proliferation studies on COLO-320DM are discussed.

PubMed: 32202790
DOI: 10.1021/acs.jmedchem.0c00045

実験手法

X-RAY DIFFRACTION (1.9 Å)