8ixs | pdb_00008ixs

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

spinqualitylabelsall models 8ixs, resolution 1.48Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8ixs is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: SO4, T6I Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function KEAP1_HUMAN Publication Abstract from PubMed 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 7 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 25, 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 25, 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. Methyl and Fluorine Effects in Novel Orally Bioavailable Keap1-Nrf2 PPI Inhibitor.,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 ACS Med Chem Lett. 2023 Apr 7;14(5):658-665. doi: 10.1021/acsmedchemlett.3c00067. , eCollection 2023 May 11. PMID:37197451 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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