8IXS

Methyl and Fluorine Effects in Novel Orally Bioavailable Keap1/Nrf2 PPI Inhibitor for Treatment of Chronic Kidney Disease

Summary for 8IXS

• Entry DOI: 10.2210/pdb8ixs/pdb
• Descriptor: Kelch-like ECH-associated protein 1, (2R,3S)-3-[[(2S)-2-fluoranyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)ethanoyl]amino]-2-methyl-3-(4-methylphenyl)propanoic acid, SULFATE ION, ... (4 entities in total)
• Functional Keywords: chronic kidney disease (ckd), keap1, nrf2, non-covalent inhibitor, peptide binding protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 35689.86

Authors

Nomura, A.,Yamaguchi, K.,Adachi, T. (deposition date: 2023-04-03, release date: 2023-06-14, Last modification date: 2024-05-29)

Primary citation

Otake, K.,Ubukata, M.,Nagahashi, N.,Ogawa, N.,Hantani, Y.,Hantani, R.,Adachi, T.,Nomura, A.,Yamaguchi, K.,Maekawa, M.,Mamada, H.,Motomura, T.,Sato, M.,Harada, K.
Methyl and Fluorine Effects in Novel Orally Bioavailable Keap1-Nrf2 PPI Inhibitor.
Acs Med.Chem.Lett., 14:658-665, 2023

PubMed Abstract: Oxidative stress is one of the causes of progression of chronic kidney disease (CKD). Activation of the antioxidant protein regulator Nrf2 by inhibition of the Keap1-Nrf2 protein-protein interaction (PPI) is of interest as a potential treatment for CKD. We report the identification of the novel and weak PPI inhibitor with good physical properties by a high throughput screening (HTS) campaign, followed by structural and computational analysis. The installation of only methyl and fluorine groups successfully provided the lead compound , which showed more than 400-fold stronger activity. Furthermore, these dramatic substituent effects can be explained by the analysis of using isothermal titration calorimetry (ITC). Thus, the resulting , which exhibited high oral absorption and durability, would be a CKD therapeutic agent because of the dose-dependent manner for up-regulation of the antioxidant protein heme oxigenase-1 (HO-1) in rat kidneys.

PubMed: 37197451
DOI: 10.1021/acsmedchemlett.3c00067

Experimental method

X-RAY DIFFRACTION (1.48 Å)