3,5-Disubstituted-indole-7-carboxamides: The discovery of a novel series of potent, selective inhibitors of IKK-β

Article · March 2011with18 Reads
DOI: 10.1016/j.bmcl.2011.02.107 · Source: PubMed
The discovery and hit-to-lead exploration of a novel series of selective IKK-β kinase inhibitors is described. The initial lead fragment 3 was identified by pharmacophore-directed virtual screening. Homology model-driven SAR exploration of the template led to potent inhibitors, such as 12, which demonstrate efficacy in cellular assays and possess encouraging developability profiles.
    • IKK-β, which is a key subunit of IKK [17], is involved in the phosphorylation of IκBα as part of the signaling pathway responsible for the transcription of NF-κB [25]. The IKK-mediated phosphorylation of the Ser32 and Ser36 residues of cytoplasmic IκBα leads to the poly-ubiquitination and subsequent proteasomal degradation of IκBα, which results in the release of NF-κB and its subsequent translocation to the nucleus [17, 18].
    [Show abstract] [Hide abstract] ABSTRACT: Background: Calotropis gigantea (Asclepiadaceae) (Niu jiao gua) has been used as a poultice in Chinese medicine for treating inflammatory skin diseases, e.g., neurodermatitis. This study aims to isolate the epidioxysterols from the flowers of C. gigantea, elucidate their structures and evaluate their possible inhibitory effects on the NF-κB pathway. Methods: The two epidioxysterols 9,11-dehydroergosterol peroxide (1) and ergosterol peroxide (2) were isolated from the powdered flowers of C. gigantea by ultrasonic-assisted extraction, followed by the purification of the crude extract by column chromatography (i.e., silica gel and MCI-gel CHP 20P open columns). The chemical structures of these compounds were identified through a comparison of their HRMS, (1)H and (13)C NMR data with those in the literature. The in vitro IKK-β inhibitory activities of compounds 1 and 2 (1-100 µM) were evaluated using an IKK α and β Assay/Inhibitor Screening Kit, which is a single-site, semi-quantitative immunoassay. Berberine was used as a positive control. The IKK-β inhibitory activities between compounds 1 and 2 were compared by a two-tailed Student's t test to summarize the structure activity relationship. Results: Compounds 1 and 2 exhibited a dose-dependent inhibitory activity towards IKK-β in a similar manner to that of berberine. The IKK-β inhibitory activities of these two epidioxysterols were significantly stronger (P = 0.001 for compound 1 and P = 0.028 for compound 2) than that of berberine at the concentration of 100 µM. Furthermore, at the same concentration the suppressive effect of compound 1 towards IKK-β was greater than that of compound 2 (P = 0.041), while their activities at 10 and 50 µM were comparable. The difference in the results at 100 µM therefore suggested that the double bond between C-9 and C-11 in compound 1 could be responsible for its higher inhibitory activity towards IKK-β at this concentration. Conclusions: 9,11-dehydroergosterol peroxide (1) and ergosterol peroxide (2) were isolated from the flowers of C. gigantea and exhibited in vitro inhibitory activities towards IKK-β.
    Full-text · Article · Dec 2016
    • For example, we have successfully identified natural product or natural product-like compounds targeting the c-myc oncogene G-quadruplex, tumor necrosis factor-alpha (TNF-α) and NEDD8-activating enzyme (NAE)293031323334. In recent years, many small molecule inhibitors of IKKβ have been identified using pharmacophore-based or high-throughput screening approaches3233343536373839 . However , the recent publication of the IKKβ X-ray crystal structure with its inhibitor [40] enables the use of powerful structure-based in silico methods for the discovery of novel IKKβ inhibitors.
    [Show abstract] [Hide abstract] ABSTRACT: Background The nuclear factor-κB (NF-κB) proteins are a small group of heterodimeric transcription factors that play an important role in regulating the inflammatory, immune, and apoptotic responses. NF-κB activity is suppressed by association with the inhibitor IκB. Aberrant NF-κB signaling activity has been associated with the development of cancer, chronic inflammatory diseases and auto-immune diseases. The IKK protein complex is comprised of IKKα, IKKβ and NEMO subunits, with IKKβ thought to play the dominant role in modulating NF-κB activity. Therefore, the discovery of new IKKβ inhibitors may offer new therapeutic options for the treatment of cancer and inflammatory diseases. Results A structure-based molecular docking approach has been employed to discover novel IKKβ inhibitors from a natural product library of over 90,000 compounds. Preliminary screening of the 12 highest-scoring compounds using a luciferase reporter assay identified 4 promising candidates for further biological study. Among these, the benzoic acid derivative (1) showed the most promising activity at inhibiting IKKβ phosphorylation and TNF-α-induced NF-κB signaling in vitro. Conclusions In this study, we have successfully identified a benzoic acid derivative (1) as a novel IKKβ inhibitor via high-throughput molecular docking. Compound 1 was able to inhibit IKKβ phosphorylation activity in vitro, and block IκBα protein degradation and subsequent NF-κB activation in human cells. Further in silico optimization of the compound is currently being conducted in order to generate more potent analogues for biological tests.
    Full-text · Article · Jan 2013
  • [Show abstract] [Hide abstract] ABSTRACT: We have discovered imidazo[1,2-b]pyridazine derivatives that show suppressive activity of inflammation in arthritis models. We optimized the substructures of imidazo[1,2-b]pyridazine derivatives to combine potent IKKβ inhibitory activity, TNFα inhibitory activity in vivo and excellent pharmacokinetics. The compound we have acquired, which had both potent activities and good pharmacokinetic profiles based on improved physicochemical properties, demonstrated efficacy on collagen-induced arthritis models in mice and rats.
    Article · Jun 2011
  • [Show abstract] [Hide abstract] ABSTRACT: A kinase-focused screening set of fragments has been assembled and has proved successful for the discovery of ligand-efficient hits against many targets. Here we present some of our general conclusions from this exercise. Notably, we present the first profiling results for literature fragments that have previously been used as starting points for optimization against individual kinases. We consider the importance of screening format and the extent to which selectivity is helpful in selecting fragments for progression. Results are also outlined for fragments targeting the DFG-out conformation and for atypical kinases such as PIM1 and lipid kinases.
    Article · Jun 2011
  • [Show abstract] [Hide abstract] ABSTRACT: 4-Alkylpyridines possessing nucleophilic β-dicarbonyl side chains have been converted to spirodihydropyridines upon treatment with ethyl chloroformate and sub-stoichiometric amounts of Ti(O(i)Pr)(4). Alternatively, inclusion of mild base in the reaction medium was found to facilitate generation of anhydrobase intermediates. Subsequent aldol-like condensations with electrophilic side chain moieties followed by hydrolysis delivered benzylically cyclized pyridines in good yield. In situ hydrogenation of cyclized anhydrobase intermediates afforded 4-substituted piperidines.
    Article · Aug 2012
  • [Show abstract] [Hide abstract] ABSTRACT: IκB kinase β (IKKβ), an attractive anti-inflammation and anti-cancer target, plays a crucial role in the activation of NF-κB signalling pathway. To identify novel IKKβ inhibitors, we combined structure-based and ligand-based methods based on the co-crystal structure of IKKβ. According to the chemical similarity, 162 reported IKKβ inhibitors were divided into five classes. For each class, a 3D pharmacophore model was established based on the binding conformations of the compounds. The validated models were further used in virtual screening. Twelve drugable compounds were retained for biological test, resulting in two novel inhibitors with IC50 values lower than 10 μM. Compared to other models, our method considers the crystal structure of IKKβ for the first time.
    Article · Feb 2013
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