Replacement of a Naphthalene Scaffold in Kelch-like ECH-Associated Protein 1 (KEAP1)/Nuclear Factor (Erythroid-derived 2)-like 2 (NRF2) Inhibitors

Richardson, Benjamin G; Jain, Atul D.; Potteti, Haranatha R.; Lazzara, Phillip R.; David, Brian P.; Tamatam, Chandra R.; Choma, Ewelina; Skowron, Kornelia J.; Dye, Katherine; Siddiqui, Zamia; Wang, Yue Ting; Krunić, Aleksej; Reddy, Sekhar P.; Moore, Terry W.

doi:10.1021/acs.jmedchem.8b01133

Cited by 44 publications

(49 citation statements)

References 60 publications

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“…compound 5. 86 Overall, 4 and 6 have been shown by X-ray crystallography to bind in the Keap1 Kelch binding pocket, and they give saturable and dose-dependent responses in SPR; thus we consider 4 and 6 to be genuine Keap1 binders. However, to minimize aggregation formations and increase precision when measuring, it is advisable to include detergent in the assay, also for these compounds.…”

Section: Discussionmentioning

confidence: 99%

A Comparative Assessment Study of Known Small-Molecule Keap1−Nrf2 Protein–Protein Interaction Inhibitors: Chemical Synthesis, Binding Properties, and Cellular Activity

et al. 2019

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Inhibiting the protein-protein interaction (PPI) between the transcription factor Nrf2 and its repressor protein Keap1 has emerged as a promising strategy to target oxidative stress in diseases, including CNS disorders. Numerous non-covalent small-molecule Keap1-Nrf2 PPI inhibitors have been reported to date, but many feature suboptimal physicochemical properties for permeating the blood-brain barrier, while others contain problematic structural moieties. Here, we present the first side-by-side assessment of all reported Keap1-Nrf2 PPI inhibitor classes using fluorescence polarization (FP), thermal shift assay (TSA), and surface plasmon resonance (SPR)-and further evaluate the compounds in an NQO1 induction cell assay and in counter tests for non-boronate ester building block 41 as the crucial carbon skeleton-building step. Synthesis of the enol triflate using the one-step NaHMDS-mediated enolization/PhNTf2-induced trapping procedure reported in the patent application 39 was not efficient in our hands, giving low yield (43% vs. 88% reported in literature 39) and significant byproduct formation. We found that using a freshly-made LiHMDS as an alternative base gave a cleaner reaction and excellent yield (quantitative). The converging SM reaction step between 38 and 41 gave several wellknown by-products, including the boronic acid, aryl boronate homo-coupling product and protodeboronation product, but could still afford the desired cross-coupling product 42 in good yield (69% vs. 33% reported in literature 39). Catalytic hydrogenation to deprotect the carboxylic acid and reduce the alkene double bond diastereoselectively furnished only the cis-cyclohexane 43 in accordance with literature; 39 this was revealed by nuclear Overhauser effect (NOE) NMR (Supporting Information Figure S1). This facial selectivity can be explained by a steric directing effect of the carboxybenzyl group. The cyclohexane carboxylic acid of 43 was finally coupled with 2-butylpyrrolidine and the pyrazole carboxylic acid deprotected to give 10 as a mixture of four stereoisomers. Attempted separation of the two diastereoisomers by preparative HPLC was unsuccessful. In the patent application, purification by HPLC is reported to give two different fractions, each containing all four stereoisomers in slightly different proportions, of which one was directly tested as a mixture. 39 Having this literature result as a reference point, we did not proceed with further purification of 10.

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Section: Discussionmentioning

confidence: 99%

A Comparative Assessment Study of Known Small-Molecule Keap1−Nrf2 Protein–Protein Interaction Inhibitors: Chemical Synthesis, Binding Properties, and Cellular Activity

et al. 2019

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“…Current PPI inhibitors are tetrahydroisoquinoline [97, 106], thiopyrimidine [107], naphthalene [108], carbazone [109], and urea derivatives [110]. Recently, the naphthalene-based nonelectrophilic PPI inhibitors were modified to develop nonnaphthalene heterocyclic scaffold based on 1,4-isoquinoline that avoids the carcinogenic and mutagenic properties of naphthalenes [111]. Some patents addressing these small molecules are presented in Table 3.…”

Section: Pharmacologic Activators Of Nrf2mentioning

confidence: 99%

Activators and Inhibitors of NRF2: A Review of Their Potential for Clinical Development

Robledinos-Antón

Fernández-Ginés

Manda

et al. 2019

Oxidative Medicine and Cellular Longevity

463

382

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The transcription factor NRF2 (nuclear factor erythroid 2-related factor 2) triggers the first line of homeostatic responses against a plethora of environmental or endogenous deviations in redox metabolism, proteostasis, inflammation, etc. Therefore, pharmacological activation of NRF2 is a promising therapeutic approach for several chronic diseases that are underlined by oxidative stress and inflammation, such as neurodegenerative, cardiovascular, and metabolic diseases. A particular case is cancer, where NRF2 confers a survival advantage to constituted tumors, and therefore, NRF2 inhibition is desired. This review describes the electrophilic and nonelectrophilic NRF2 activators with clinical projection in various chronic diseases. We also analyze the status of NRF2 inhibitors, which at this time provide proof of concept for blocking NRF2 activity in cancer therapy.

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“…It has been reported that Nrf2 activators can bind to Keap1 and induce conformational changes in Keap1. This may block ubiquitin-mediated Nrf2 degradation in the cytosol, leading to subsequent nuclear translocation of Nrf2 31 . Thus, we investigated the potential capability of (+)-CLA on binding to the Keap1 protein using a cellular thermal shift assay.…”

Section: (+)-Cla Targets Keap1-cys151 To Inhibit Nrf2 Ubiquitylationmentioning

confidence: 99%

(+)-Clausenamide protects against drug-induced liver injury by inhibiting hepatocyte ferroptosis

Wang

Liu

et al. 2020

Cell Death Dis

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Drug-induced liver injury is the major cause of acute liver failure. However, the underlying mechanisms seem to be multifaceted and remain poorly understood, resulting in few effective therapies. Here, we report a novel mechanism that contributes to acetaminophen-induced hepatotoxicity through the induction of ferroptosis, a distinctive form of programmed cell death. We subsequently identified therapies protective against acetaminophen-induced liver damage and found that (+)-clausenamide ((+)-CLA), an active alkaloid isolated from the leaves of Clausena lansium (Lour.) Skeels, inhibited acetaminophen-induced hepatocyte ferroptosis both in vivo and in vitro. Consistently, (+)-CLA significantly alleviated acetaminophen-induced or erastin-induced hepatic pathological damages, hepatic dysfunctions and excessive production of lipid peroxidation both in cultured hepatic cell lines and mouse liver. Furthermore, treatment with (+)-CLA reduced the mRNA level of prostaglandin endoperoxide synthase 2 while it increased the protein level of glutathione peroxidase 4 in hepatocytes and mouse liver, confirming that the inhibition of ferroptosis contributes to the protective effect of (+)-CLA on drug-induced liver damage. We further revealed that (+)-CLA specifically reacted with the Cys-151 residue of Keap1, which blocked Nrf2 ubiquitylation and resulted in an increased Nrf2 stability, thereby leading to the activation of the Keap1–Nrf2 pathway to prevent drug-induced hepatocyte ferroptosis. Our studies illustrate the innovative mechanisms of acetaminophen-induced liver damage and present a novel intervention strategy to treat drug overdose by using (+)-CLA.

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Replacement of a Naphthalene Scaffold in Kelch-like ECH-Associated Protein 1 (KEAP1)/Nuclear Factor (Erythroid-derived 2)-like 2 (NRF2) Inhibitors

Cited by 44 publications

References 60 publications

A Comparative Assessment Study of Known Small-Molecule Keap1−Nrf2 Protein–Protein Interaction Inhibitors: Chemical Synthesis, Binding Properties, and Cellular Activity

A Comparative Assessment Study of Known Small-Molecule Keap1−Nrf2 Protein–Protein Interaction Inhibitors: Chemical Synthesis, Binding Properties, and Cellular Activity

Activators and Inhibitors of NRF2: A Review of Their Potential for Clinical Development

(+)-Clausenamide protects against drug-induced liver injury by inhibiting hepatocyte ferroptosis

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