8XGV

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

This is a non-PDB format compatible entry.

Summary for 8XGV

• Entry DOI: 10.2210/pdb8xgv/pdb
• Descriptor: 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)
• 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: 35733.92

Authors

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. (deposition date: 2023-12-15, release date: 2024-05-22)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.42 Å)