Binding Mode and Structure–Activity Relationships around Direct Inhibitors of the Nrf2–Keap1 Complex

Jnoff, Eric; Albrecht, Claudia; Barker, John J.; Barker, Oliver; Beaumont, Edward; Bromidge, Steven M.; Brookfield, Frederick A.; Brooks, Mark A.; Bubert, Christian; Ceska, Tom; Corden, Vincent; Dawson, Graham; Duclos, Stéphanie; Fryatt, Tara; Génicot, Christophe; Jigorel, Émilie; Kwong, Jason C; Maghames, Rosemary; Mushi, Innocent; Pike, Richard K; Sands, Zara A.; Smith, M. A.; Stimson, Christopher C.; Courade, Jean-Philippe

doi:10.1002/cmdc.201300525

Cited by 131 publications

(143 citation statements)

References 26 publications

(5 reference statements)

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“…The carboxamide group, which can form a similar hydrogen bond but has a significantly high pK a value, resulted in the inactive compound. This is consistent with the results provided by Jnoff et al 29 However, the carboxamide group can also be active in certain cases. The research of Jain et al 30 showed that when the substituent on the side-chain phenyl ring was the p-methoxy group, the diacetamide moiety can insert into the P1 and P2 subpockets and good inhibition activity can be retained.…”

Section: Potent Ppi Inhibition Activitysupporting

confidence: 93%

Polar Recognition Group Study of Keap1-Nrf2 Protein–Protein Interaction Inhibitors

Tan

et al. 2016

ACS Med. Chem. Lett.

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Directly disrupting the Keap1-Nrf2 protein−protein interaction (PPI) has emerged as an attractive way to activate Nrf2, and Keap1-Nrf2 PPI inhibitors have been proposed as potential agents to relieve inflammatory and oxidative stress diseases. In this work, we investigated the diacetic moiety around the potent Keap1-Nrf2 PPI inhibitor DDO1018 (2), which was reported by our group previously. Exploration of bioisosteric replacements afforded the ditetrazole analog 7, which maintains the potent PPI inhibition activity (IC 50 = 15.8 nM) in an in vitro fluorescence polarization assay. Physicochemical property determination demonstrated that ditetrazole replacement can improve the drug-like property, including elevation of pK a , log D, and transcellular permeability. Additionally, 7 is more efficacious than 2 on inducing the expression of Nrf2-dependent gene products in cells. This study provides an alternative way to replace the diacetic moiety and occupy the polar subpockets in Keap1, which can benefit the subsequent development of Keap1-Nrf2 PPI inhibitor.

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Section: Potent Ppi Inhibition Activitysupporting

confidence: 93%

Polar Recognition Group Study of Keap1-Nrf2 Protein–Protein Interaction Inhibitors

Tan

et al. 2016

ACS Med. Chem. Lett.

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“…Systems Medicine Approach to NRF2 in Chronic Diseases Five families of PPI inhibitors have been described: tetrahydroisoquinoline (Jnoff et al, 2014;Richardson et al, 2015), thiopyrimidine (Marcotte et al, 2013), naphthalene (Jiang et al, 2014b), carbazone (Ranjan et al, 2014), and urea derivatives (Sato et al, 2013). Table 3 compiles recent patents addressing these small molecules.…”

Section: B Protein-protein Interaction Inhibitors For Nuclear Factormentioning

confidence: 99%

“…From the large number of compounds indexed in the available libraries, the compounds LH601, benzenesulfonylpyrimidone 2, N-phenyl-benzenesulfonamide, and a series of 1,4-diphenyl-1,2,3-triazoles might be very well-suited candidates to inhibit the PPI with KEAP1 (Hu et al, 2013;Jnoff et al, 2014;Bertrand et al, 2015;Wen et al, 2015;Nasiri et al, 2016). These studies described in detail the atomic interaction with KEAP1, the affinity, and the thermodynamics parameters of binding.…”

Section: B Protein-protein Interaction Inhibitors For Nuclear Factormentioning

confidence: 99%

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

et al. 2018

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“…Limited variations to the structure resulted in compounds with a similar overall Keap1-binding affinity in the 1-2 μM range. The effect of these changes was rationalized using a series of crystal structures that demonstrated a binding orientation in which the tetrahydroisoquinoline occupies space in the channel that passes through the centre of the Kelch β-propeller structure [36].…”

Section: Tetrahydroisoquinolinesmentioning

confidence: 99%

Peptide and small molecule inhibitors of the Keap1–Nrf2 protein–protein interaction

Wells

2015

Biochemical Society Transactions

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The transcription factor nuclear factor erythroid-2-related factor 2 (Nrf2) up-regulates the expression of a range of cytoprotective enzymes with antioxidant response elements in their promoter regions and thus can protect cells against oxidative damage. Increasing Nrf2 activity has been proposed as a therapeutic intervention in a range of chronic neurodegenerative conditions and cancer chemoprevention. One of the main mechanisms by which Nrf2 is negatively regulated involves an interaction with the ubiquitination facilitator protein, Kelch-like ECH-associated protein 1 (Keap1) that facilitates degradation of Nrf2. Inhibition of this process underlies the mode of action of a broad group of compounds that increase Nrf2 activity. A number of natural products, including the isothiocyanate sulforaphane, up-regulate Nrf2 by interacting with Keap1 in a covalent manner to stall its activity. Recently, a number of peptide and small molecule inhibitors of the protein-protein interaction (PPI) between Keap1 and Nrf2 have been described. These classes of compound have contrasting modes of action at the molecular level and there is emerging evidence that their biological activities have similarities and differences. This review describes the various classes of PPI inhibitor that have been described in the literature and the biological evaluations that have been performed.

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Binding Mode and Structure–Activity Relationships around Direct Inhibitors of the Nrf2–Keap1 Complex

Cited by 131 publications

References 26 publications

Polar Recognition Group Study of Keap1-Nrf2 Protein–Protein Interaction Inhibitors

Polar Recognition Group Study of Keap1-Nrf2 Protein–Protein Interaction Inhibitors

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

Peptide and small molecule inhibitors of the Keap1–Nrf2 protein–protein interaction

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