8IVG
Methyl and Fluorine Effects in Novel Orally Bioavailable Keap1/Nrf2 PPI Inhibitor for Treatment of Chronic Kidney Disease
Summary for 8IVG
| Entry DOI | 10.2210/pdb8ivg/pdb |
| Descriptor | Kelch-like ECH-associated protein 1, (3S)-3-(4-methylphenyl)-3-[2-(5,6,7,8-tetrahydronaphthalen-2-yl)ethanoylamino]propanoic acid, 2,3-DIHYDROXY-1,4-DITHIOBUTANE, ... (5 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 | 36100.28 |
| Authors | 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. (deposition date: 2023-03-27, 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 Cited by 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: 37197451DOI: 10.1021/acsmedchemlett.3c00067 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.8 Å) |
Structure validation
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