Discovery of benzo[g]indoles as a novel class of non-covalent Keap1-Nrf2 protein-protein interaction inhibitor

Yasuda, Daisuke; Yuasa, Akihiro; Obata, Rika; Nakajima, Mao; 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.2017.10.008

Cited by 27 publications

(45 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…24,28 Compounds 1-11 all showed robust inhibition (Figure 2A) with Ki values correlating with literature ( Figure 1 vs. Table 1). 22,24,27,28,30,34,36,37,39 Only compounds 8 and 11 showed some deviations from the literature (Ki = 0.0021 µM vs. IC50 = 0.20 µM 38 and Ki = 2.8 µM vs. IC50 = 118 µM 33 , respectively). For compound 8, this difference can be explained by a high protein-to-probe concentration ratio in the reported FP assay (250 nM Keap1 to 10 nM probe) compared to our conditions (14 nM Keap1 to 3 nM probe); this is despite using the same peptide probe.…”

Section: Inhibition Activity In Competitive Fp Assaymentioning

confidence: 91%

“…. 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%

“…For compound 8, this difference can be explained by a high protein-to-probe concentration ratio in the reported FP assay (250 nM Keap1 to 10 nM probe) compared to our conditions (14 nM Keap1 to 3 nM probe); this is despite using the same peptide probe. 38 Thus, considering the affinity of the probe, such conditions would give rise to a significantly higher IC50 value than the Ki. 38,65 In fact, using the reported protein and probe concentrations and assuming a Kd of 10 nM for the probe, a Ki ≈ 2 nM can be calculated from their measured IC50 value of 0.20 µM, which is in line with our result.…”

Section: Inhibition Activity In Competitive Fp Assaymentioning

confidence: 99%

“…Ghorab et al 45 ; 18: Sun et al 46 ; 19-21: Zhuang et al 35 Figure 1A). 22,24,[27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46] Additionally, a number of inhibitors (3, 4, 6, 7, 9, 11, and 14) have been confirmed by X-ray crystallography to bind the Kelch domain (see examples in Figure 1B). 10 However, since the Kelch binding pocket is still rather large compared to classical enzyme or receptor pockets and contains multiple arginine residues ( Figure 1B), bulky ligands featuring carboxylic acids have been enriched in medicinal chemistry programs.…”

Section: Introductionmentioning

confidence: 98%

“…Marcotte et al 33 , Jiang et al 22 , Jain et al 34 , Zhuang et al 35 ; 5: Jiang et al 22 ; Jain et al 34 ; Bresciani et al 31 ; 6: Jain et al 34 ; 7: Winkel et al 36 , Szill et al 37 ; 8: Yasuda et al 38 ; 9: Davies et al 27 ; 10: Callahan et al 39 ; 11: Marcotte et al 33 ; 12: Bertrand et al 40 ; 13: Kazantsev et al 41 ; 14: Satoh et al 42 ; 15: Shimozono et al 43 ; 16: Xu et al 44 ; 17:…”

Section: Introductionunclassified

See 4 more Smart Citations

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

et al. 2019

View full text Add to dashboard Cite

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.

show abstract

Section: Inhibition Activity In Competitive Fp Assaymentioning

confidence: 91%

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

confidence: 99%

Section: Inhibition Activity In Competitive Fp Assaymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Section: Introductionunclassified

See 3 more Smart Citations

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

et al. 2019

View full text Add to dashboard Cite

show abstract

A Catalytic Construction of Indoles via Formation of Ruthenium Vinylidene Species from N‐Arylynamides

et al. 2020

View full text Add to dashboard Cite

Treatment of ynamides with a catalytic amount of TpRuCl(PPh3)2 resulted in the construction of indole scaffolds known as privileged structure motifs. This reaction involved a cascade of 1,2‐rearrangement and cyclization carrying out C−C bond formation via a ruthenium vinylidene intermediate, as revealed by a deuterium‐labeling experiments. Furthermore, the transformation of multi‐functionalized ynamide, derived from a practical drug molecule, showed a high functional group tolerance of this reaction.

show abstract

KEAP1‐NRF2 protein–protein interaction inhibitors: Design, pharmacological properties and therapeutic potential

Crisman

Duarte

Daudén

et al. 2022

Medicinal Research Reviews

View full text Add to dashboard Cite

show abstract

Discovery of benzo[g]indoles as a novel class of non-covalent Keap1-Nrf2 protein-protein interaction inhibitor

Cited by 27 publications

References 24 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

A Catalytic Construction of Indoles via Formation of Ruthenium Vinylidene Species from N‐Arylynamides

KEAP1‐NRF2 protein–protein interaction inhibitors: Design, pharmacological properties and therapeutic potential

Contact Info

Product

Resources

About