6TKR

Tankyrase 2 in complex with an inhibitor (OM-1704)

これはPDB形式変換不可エントリーです。

6TKR の概要

• エントリーDOI: 10.2210/pdb6tkr/pdb
• 分子名称: Tankyrase-2, ~{N}-[3-[5-(5-ethoxypyridin-2-yl)-4-(2-fluorophenyl)-1,2,4-triazol-3-yl]cyclobutyl]-1,5-naphthyridine-2-carboxamide, ZINC ION, ... (4 entities in total)
• 機能のキーワード: inhibitor, complex, poly-adp-ribosylation, enzyme, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 55749.41

構造登録者

Sowa, S.T.,Lehtio, L. (登録日: 2019-11-28, 公開日: 2020-07-08, 最終更新日: 2024-01-24)

主引用文献

Waaler, J.,Leenders, R.G.G.,Sowa, S.T.,Alam Brinch, S.,Lycke, M.,Nieczypor, P.,Aertssen, S.,Murthy, S.,Galera-Prat, A.,Damen, E.,Wegert, A.,Nazare, M.,Lehtio, L.,Krauss, S.
Preclinical Lead Optimization of a 1,2,4-Triazole Based Tankyrase Inhibitor.
J.Med.Chem., 63:6834-6846, 2020

PubMed Abstract: Tankyrases 1 and 2 are central biotargets in the WNT/β-catenin signaling and Hippo signaling pathways. We have previously developed tankyrase inhibitors bearing a 1,2,4-triazole moiety and binding predominantly to the adenosine binding site of the tankyrase catalytic domain. Here we describe a systematic structure-guided lead optimization approach of these tankyrase inhibitors. The central 1,2,4-triazole template and cyclobutyl linker of the lead compound were left unchanged, while side-group East, West, and South moieties were altered by introducing different building blocks defined as point mutations. The systematic study provided a novel series of compounds reaching picomolar IC inhibition in WNT/βcatenin signaling cellular reporter assay. The novel optimized lead resolves previous atropisomerism, solubility, and Caco-2 efflux liabilities. shows a favorable ADME profile, including improved Caco-2 permeability and oral bioavailability in mice, and exhibits antiproliferative efficacy in the colon cancer cell line COLO 320DM

PubMed: 32511917
DOI: 10.1021/acs.jmedchem.0c00208

実験手法

X-RAY DIFFRACTION (2.75 Å)