Isoquinoline Kelch-like ECH-Associated Protein 1-Nuclear Factor (Erythroid-Derived 2)-like 2 (KEAP1-NRF2) Inhibitors with High Metabolic Stability

Lazzara, Phillip R.; David, Brian P.; Ankireddy, Aparna; Richardson, Benjamin G; Dye, Katherine; Ratia, Kiira; Reddy, Sekhar P.; Moore, Terry W.

doi:10.1021/acs.jmedchem.9b01074

Cited by 35 publications

(41 citation statements)

References 45 publications

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“…The classical NQO1 inducers are primarily oxidants and electrophiles or other compounds that react (or are metabolized to products that react) and chemically modify cysteine sensors of Keap1 [ 43 ]. A new generation of NQO1 inducers is also emerging, that of noncovalent small-molecule modulators of the Keap1–Nrf2 protein-protein interaction [ [44] , [45] , [46] ]. Because our diiodoquinazolinones have some common features with the Keap1–Nrf2 protein-protein interaction inhibitors, in this study we tested the potential ability of these compounds to directly disrupt the binding of Keap1 to Nrf2 by molecular modeling (see section 2.3 ).…”

Section: Resultsmentioning

confidence: 99%

Radiomodulatory effect of a non-electrophilic NQO1 inducer identified in a screen of new 6, 8-diiodoquinazolin-4(3H)-ones carrying a sulfonamide moiety

Soliman

Karam

Mekkawy

et al. 2020

European Journal of Medicinal Chemistry

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Fifteen new quinazolinone derivatives bearing benzenesulfonamide moiety with variable acetamide tail were synthesized. The structures assigned to the products were concordant with the microanalytical and spectral data. Compounds 4–18 were screened for their ability to induce the antioxidant enzyme NAD(P)H: quinone oxidoreductase 1 (NQO1) in cells, a classical target for transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2). The 2-((6,8-diiodo-4-oxo-3-(4-sulfamoylphenyl)-3,4-dihydroquinazolin-2-yl)thio)- N -(3,4,5-trimethoxyphenyl) acetamide 15 showed the most potent NQO1 inducer activity in vitro . Compound 15 had low toxicity in mice (LD 50 = 500 mg/kg). It also reduced the damaging effects of gamma radiation, as assessed by the levels of Nrf2, NQO1, reactive oxygen species (ROS) and malondialdehyde (MDA) in liver tissues. In addition, compound 15 showed amelioration in the complete blood count of irradiated mice and enhanced survival over a period of 30 days following irradiation. Molecular docking of 15 inside the Nrf2-binding site of Kelch-like ECH associated protein 1 (Keap1), the main negative regulator of Nrf2, showed the same binding interactions as that of the co-crystallized ligand considering the binding possibilities and energy scores. These findings suggest that compound 15 could be considered as a promising antioxidant and radiomodulatory agent.

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Section: Resultsmentioning

confidence: 99%

Radiomodulatory effect of a non-electrophilic NQO1 inducer identified in a screen of new 6, 8-diiodoquinazolin-4(3H)-ones carrying a sulfonamide moiety

Soliman

Karam

Mekkawy

et al. 2020

European Journal of Medicinal Chemistry

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“…To this end, high-throughput screening, fragment-based discovery, and structurebased virtual screening have all been used to identify compounds which can compete with NRF2 for binding with KEAP1, resulting in the stabilization of NRF2 and the upregulation of its ARE-dependent gene signature (158)(159)(160)(161)(162)(163)(164). One such PPI compound, named compound 7, is able to induce NQO1 expression with a half-maximal effective concentration (EC 50 ) of 12 nM, which is comparable to those of potent electrophile inducers; this therefore suggests that the utilization of a PPI-based approach may be a viable complementary strategy for NRF2 activation (162).…”

Section: Regulation Of Nrf2 Activity By P62 Through the Hinge-and-latch Mechanismmentioning

confidence: 99%

The Molecular Mechanisms Regulating the KEAP1-NRF2 Pathway

Baird

Yamamoto

2020

Molecular and Cellular Biology

831

513

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The KEAP1-NRF2 pathway is the principal protective response to oxidative and electrophilic stresses. Under homeostatic conditions, KEAP1 forms part of an E3 ubiquitin ligase, which tightly regulates the activity of the transcription factor NRF2 by targeting it for ubiquitination and proteasome-dependent degradation. In response to stress, an intricate molecular mechanism facilitated by sensor cysteines within KEAP1 allows NRF2 to escape ubiquitination, accumulate within the cell, and translocate to the nucleus, where it can promote its antioxidant transcription program. Recent advances have revealed that KEAP1 contains multiple stress sensors and inactivation modalities, which together allow diverse cellular inputs, from oxidative stress and cellular metabolites to dysregulated autophagy, to regulate NRF2 activity. This integration of the KEAP1-NRF2 system into multiple cellular signaling and metabolic pathways places NRF2 activation as a critical regulatory node in many disease phenotypes and suggests that the pharmaceutical modulation of NRF2’s cytoprotective activity will be beneficial for human health in a broad range of noncommunicable diseases.

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“…Moreover, experimental evidence suggests that the maximally tolerated dose of sulforaphane (and other electrophiles) is not necessarily the most effective [ 114 ]. This realization is driving research that aims to identify non-electrophilic NRF2 activators, which inhibit binding to KEAP1, and where promising candidates are emerging [ 71 , 115 , 116 ].…”

Section: Concluding Remarks and Future Perspectivesmentioning

confidence: 99%

Can Activation of NRF2 Be a Strategy against COVID-19?

Cuadrado

Pajares

Benito

et al. 2020

Trends in Pharmacological Sciences

181

183

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Acute respiratory distress syndrome (ARDS) caused by SARS-CoV-2 is largely the result of a dysregulated host response, followed by damage to alveolar cells and lung fibrosis. Exacerbated proinflammatory cytokines release (cytokine storm) and loss of T lymphocytes (leukopenia) characterize the most aggressive presentation. We propose that a multifaceted anti-inflammatory strategy based on pharmacological activation of nuclear factor erythroid 2 p45-related factor 2 (NRF2) can be deployed against the virus. The strategy provides robust cytoprotection by restoring redox and protein homeostasis, promoting resolution of inflammation, and facilitating repair. NRF2 activators such as sulforaphane and bardoxolone methyl are already in clinical trials. The safety and efficacy information of these modulators in humans, together with their well-documented cytoprotective and anti-inflammatory effects in preclinical models, highlight the potential of this armamentarium for deployment to the battlefield against COVID-19.

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Isoquinoline Kelch-like ECH-Associated Protein 1-Nuclear Factor (Erythroid-Derived 2)-like 2 (KEAP1-NRF2) Inhibitors with High Metabolic Stability

Cited by 35 publications

References 45 publications

Radiomodulatory effect of a non-electrophilic NQO1 inducer identified in a screen of new 6, 8-diiodoquinazolin-4(3H)-ones carrying a sulfonamide moiety

Radiomodulatory effect of a non-electrophilic NQO1 inducer identified in a screen of new 6, 8-diiodoquinazolin-4(3H)-ones carrying a sulfonamide moiety

The Molecular Mechanisms Regulating the KEAP1-NRF2 Pathway

Can Activation of NRF2 Be a Strategy against COVID-19?

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