6TYP

KEAP1 Kelch domain in complex with Compound 2

6TYP の概要

• エントリーDOI: 10.2210/pdb6typ/pdb
• 分子名称: Kelch-like ECH-associated protein 1, FORMIC ACID, (3S)-3-[2-(benzenecarbonyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-3-(1-ethyl-4-methyl-1H-benzotriazol-5-yl)propanoic acid, ... (4 entities in total)
• 機能のキーワード: keap1 kelch domain, peptide binding protein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 32582.42

構造登録者

Marcotte, D.J. (登録日: 2019-08-09, 公開日: 2020-01-15, 最終更新日: 2024-11-06)

主引用文献

Ma, B.,Lucas, B.,Capacci, A.,Lin, E.Y.,Jones, J.H.,Dechantsreiter, M.,Enyedy, I.,Marcotte, D.,Xiao, G.,Li, B.,Richter, K.
Design, synthesis and identification of novel, orally bioavailable non-covalent Nrf2 activators.
Bioorg.Med.Chem.Lett., 30:126852-126852, 2020

PubMed Abstract: Nrf2 is a transcription factor regulating expression of the Phase II Antioxidant Response and plays an important role in neuroprotection and detoxification. Nrf2 activation is inhibited by interaction with Keap1. Covalent Keap1 inhibitors such as dimethyl fumarate (DMF) and RTA-408 are either on the market or in late stage clinical trials which implies potential benefit of Nrf2 activation. Activation of Nrf2 by disrupting Nrf2-Keap1 interaction through a non-covalent small molecule is an attractive approach with the promise of greater selectivity. However, there are no known non-covalent Nrf2 activators with acceptable pharmacokinetic properties to test the hypothesis in vivo. Based on our early reported work, using structural-based design, followed by extensive SAR exploration, we have identified a novel series of non-covalent Nrf2 activators, with sub-nanomolar binding affinity on Keap1 and single digit nanomolar activity in an astrocyte assay. A representative analog shows excellent oral PK and good Nrf2-dependent gene inductions in kidney. These results provide a peripheral in vivo tool compound to validate the biology of non-covalent activation of Nrf2.

PubMed: 31898999
DOI: 10.1016/j.bmcl.2019.126852

実験手法

X-RAY DIFFRACTION (2.5 Å)