4XMB

Crystal structure of 2,2'-(naphthalene-1,4-diylbis(((4-methoxyphenyl)sulfonyl)azanediyl))diacetamide bound to human Keap1 Kelch domain

Summary for 4XMB

• Entry DOI: 10.2210/pdb4xmb/pdb
• Descriptor: Kelch-like ECH-associated protein 1, 2,2'-(naphthalene-1,4-diylbis(((4-methoxyphenyl)sulfonyl)azanediyl))diacetamide (3 entities in total)
• Functional Keywords: nrf2 activators, cul3, cullin3, btb, protein binding
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm: Q14145
• Total number of polymer chains: 1
• Total formula weight: 32267.05

Authors

Luciano, J.P.,Ryuzoji, A.F.,Mesecar, A.D. (deposition date: 2015-01-14, release date: 2015-09-30, Last modification date: 2023-09-27)

Primary citation

Jain, A.D.,Potteti, H.,Richardson, B.G.,Kingsley, L.,Luciano, J.P.,Ryuzoji, A.F.,Lee, H.,Krunic, A.,Mesecar, A.D.,Reddy, S.P.,Moore, T.W.
Probing the structural requirements of non-electrophilic naphthalene-based Nrf2 activators.
Eur.J.Med.Chem., 103:252-268, 2015

PubMed Abstract: Activation of the transcription factor Nrf2 has been posited to be a promising therapeutic strategy in a number of inflammatory and oxidative stress diseases due to its regulation of detoxifying enzymes. In this work, we have developed a comprehensive structure-activity relationship around a known, naphthalene-based non-electrophilic activator of Nrf2, and we report highly potent non-electrophilic activators of Nrf2. Computational docking analysis of a subset of the compound series demonstrates the importance of water molecule displacement for affinity, and the X-ray structure of di-amide 12e supports the computational analysis. One of the best compounds, acid 16b, has an IC50 of 61 nM in a fluorescence anisotropy assay and a Kd of 120 nM in a surface plasmon resonance assay. Additionally, we demonstrate that the ethyl ester of 16b is an efficacious inducer of Nrf2 target genes, exhibiting ex vivo efficacy similar to the well-known electrophilic activator, sulforaphane.

PubMed: 26363505
DOI: 10.1016/j.ejmech.2015.08.049

Experimental method

X-RAY DIFFRACTION (2.428 Å)