8XGV

Optimization Efforts for Identification of Novel Highly Potent Keap1-Nrf2 Protein-Protein Interaction (PPI) Inhibitors

これはPDB形式変換不可エントリーです。

8XGV の概要

• エントリーDOI: 10.2210/pdb8xgv/pdb
• 分子名称: Kelch-like ECH-associated protein 1, (2~{R},3~{S})-3-[[(2~{S})-2-[4-[(3-ethoxypyridin-2-yl)methyl]phenyl]-2-fluoranyl-ethanoyl]amino]-2-methyl-3-(4-methylphenyl)propanoic acid, ACETATE ION, ... (5 entities in total)
• 機能のキーワード: chronic kidney disease (ckd), keap1, nrf2, non-covalent inhibitor, 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: 35733.92

構造登録者

Otake, K.,Hara, Y.,Ubukata, M.,Inoue, M.,Nagahashi, N.,Motoda, D.,Ogawa, N.,Hantani, Y.,Hantani, R.,Adachi, T.,Nomura, A.,Yamaguchi, K.,Maekawa, M.,Mamada, H.,Motomura, T.,Sato, M.,Harada, K. (登録日: 2023-12-15, 公開日: 2024-05-22)

主引用文献

Otake, K.,Hara, Y.,Ubukata, M.,Inoue, M.,Nagahashi, N.,Motoda, D.,Ogawa, N.,Hantani, Y.,Hantani, R.,Adachi, T.,Nomura, A.,Yamaguchi, K.,Maekawa, M.,Mamada, H.,Motomura, T.,Sato, M.,Harada, K.
Optimization Efforts for Identification of Novel Highly Potent Keap1-Nrf2 Protein-Protein Interaction Inhibitors.
J.Med.Chem., 67:3741-3763, 2024

PubMed Abstract: In research focused on protein-protein interaction (PPI) inhibitors, the optimization process to achieve both high inhibitory activity and favorable physicochemical properties remains challenging. Our previous study reported the discovery of novel and bioavailable Keap1-Nrf2 PPI inhibitor which exhibited moderate in vivo activity in rats. In this work, we present our subsequent efforts to optimize this compound. Two distinct approaches were employed, targeting high energy water molecules and Ser602 as "hot spots" from the anchor with good aqueous solubility, metabolic stability, and membrane permeability. Through ligand efficiency (LE)-guided exploration, we identified two novel inhibitors and with good pharmacokinetics (PK) profiles and more potent in vivo activities, which appear to be promising chemical probes among the existing inhibitors.

PubMed: 38408347
DOI: 10.1021/acs.jmedchem.3c02171

実験手法

X-RAY DIFFRACTION (1.42 Å)