Synthesis of Keap1-phosphorylated p62 and Keap1-Nrf2 protein-protein interaction inhibitors and their inhibitory activity

Yasuda, Daisuke; Nakajima, Mao; Yuasa, Akihiro; Obata, Rika; Takahashi, Kyoko; Ohe, Tomoyuki; Ichimura, Yoshinobu; Komatsu, Masaaki; Yamamoto, Masayuki; Imamura, Riyo; Kojima, Hirotatsu; Okabe, Takayoshi; Nagano, Tetsuo; Mashino, Tadahiko

doi:10.1016/j.bmcl.2016.10.083

Cited by 39 publications

(35 citation statements)

References 21 publications

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“…High-throughput screening and fragment-based drug discovery identified structures from which several PPIi were synthesized and evaluated. This is the case of Cpd16 and its more active derivatives Cpd16-AA and the acetonyl-naphtalene and ethoxy-derivative K67 [ 131 , 132 ] ( Figure 4 B). K67 is of particular interest in this series due to, first, a better selectivity index for direct binding to Nrf2 rather than to phospho-p62 protein, another protein interacting with Keap1, and, second, to its inhibitory activity on cell proliferation and on resistance to cisplatin and sorafenib from comparison to Cpd16 [ 132 ].…”

Section: Targeting Transcription Factor At the Protein/protein Intmentioning

confidence: 92%

Targeting Transcription Factors for Cancer Treatment

et al. 2018

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Transcription factors are involved in a large number of human diseases such as cancers for which they account for about 20% of all oncogenes identified so far. For long time, with the exception of ligand-inducible nuclear receptors, transcription factors were considered as “undruggable” targets. Advances knowledge of these transcription factors, in terms of structure, function (expression, degradation, interaction with co-factors and other proteins) and the dynamics of their mode of binding to DNA has changed this postulate and paved the way for new therapies targeted against transcription factors. Here, we discuss various ways to target transcription factors in cancer models: by modulating their expression or degradation, by blocking protein/protein interactions, by targeting the transcription factor itself to prevent its DNA binding either through a binding pocket or at the DNA-interacting site, some of these inhibitors being currently used or evaluated for cancer treatment. Such different targeting of transcription factors by small molecules is facilitated by modern chemistry developing a wide variety of original molecules designed to specifically abort transcription factor and by an increased knowledge of their pathological implication through the use of new technologies in order to make it possible to improve therapeutic control of transcription factor oncogenic functions.

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Section: Targeting Transcription Factor At the Protein/protein Intmentioning

confidence: 92%

Targeting Transcription Factors for Cancer Treatment

et al. 2018

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“…. 22,34,36,38,56 A key issue with these syntheses lies in the poor stability of the 1,4-diamino intermediates 30 and 33, which were observed to rapidly degrade, presumably through oxidation; this might explain the reproducibility issues in terms of yields, i.e. the previously reported yield for the synthesis of 4 (64%) could not be replicated here (13-23%), which also applies for compound 7 (overall yield of 15% vs. literature yield of 35%).…”

Section: Selection and Synthesis Of Known Small-molecule Keap1-nrf2 Pmentioning

confidence: 99%

“…. The compound was synthesized according to previously described procedure 56 Benzyl 3-oxocyclohexane-1-carboxylate (37). The compound was synthesized in three steps using previously described procedures 39,90 with some deviations.…”

Section: Nn'-((1z4z)-naphthalene-14-diylidene)bis(4-ethoxybenzenesmentioning

confidence: 99%

“…No further purification or characterization was performed, and the next step carried out immediately after due to the rapid degradation of the diamine.N,N'-(naphthalene-1,4-diyl)bis(4-ethoxybenzenesulfonamide) (34). The compound was synthesized according to previously described procedure56 with minor deviations. To a solution of 30 (0.32 g, 2.02 mmol, 1.0 equiv prepared freshly) in DCM (5.0 mL) was added pyridine (1.07 mL, 13.22 mmol, 6.5 equiv) followed by 4ethoxybenzenesulfonyl chloride (1.00 g, 4.53 mmol, 2.2 equiv).…”

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confidence: 99%

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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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“…KEAP1, β-transducin repeat-containing protein (β-TRCP), or HRD1), although currently there are no established compounds capable of achieving this effect. Furthermore, an inhibitor of the phospho-p62-KEAP1 interaction that does not directly affect KEAP1-NRF2 binding has recently been discovered [43], implying that compounds targeting the p62-KEAP1 interaction can be utilized to prevent the non-canonical upregulation of NRF2. Therefore, discovering novel inhibitors of NRF2 or its target proteins, or developing novel compounds that enhance the negative regulation and degradation of NRF2 could prove useful in re-establishing physiological NRF2 signaling (Figure 1B).…”

Section: Possible Therapeutic Strategiesmentioning

confidence: 99%

Non-Canonical Activation of NRF2: New Insights and Its Relevance to Disease

Dodson

Zhang

2017

Curr Pathobiol Rep

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Purpose of review The goal of this review is to summarize the current knowledge in the field regarding the non-canonical activation of the NRF2 pathway. Specifically, we address what role p62 plays in mediating this pathway, which pathologies have been linked to the p62-dependent activation of NRF2, as well as what therapeutic strategies could be used to treat diseases associated with the non-canonical pathway. Recent findings It has recently been shown that autophagic dysfunction leads to the aggregation or autophagosomal accumulation of p62, which sequesters KEAP1, resulting in prolonged activation of NRF2. The ability of p62 to outcompete NRF2 for KEAP1 binding depends on its abundance, or post-translational modifications to its key domains. Furthermore, the relevance of the p62-dependent activation of NRF2 in disease has been demonstrated in human hepatocellular carcinomas, as well as neurodegenerative diseases. Summary These findings indicate that targeting p62, or the enzymes that modify it, could prove to be an advantageous strategy for treating diseases associated with autophagy dysregulation and prolonged activation of NRF2. Other therapeutic possibilities include restoring proper autophagic function, or directly inhibiting NRF2 or its targets, to restore redox and metabolic homeostasis. Future studies will help further clarify the mechanisms, regulation, and relevance of the non-canonical pathway in driving disease pathogenesis.

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Synthesis of Keap1-phosphorylated p62 and Keap1-Nrf2 protein-protein interaction inhibitors and their inhibitory activity

Cited by 39 publications

References 21 publications

Targeting Transcription Factors for Cancer Treatment

Targeting Transcription Factors for Cancer Treatment

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

Non-Canonical Activation of NRF2: New Insights and Its Relevance to Disease

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