Identification of new inhibitors of protein kinase R guided by statistical modeling

Bryk, Ruslana; Wu, Kangyun; Raimundo, Brian C.; Boardman, Paul E.; Chao, Ping; Conn, Graeme L.; Anderson, Eric H.; Cole, James L.; Duffy, Nigel; Nathan, Carl; Griffin, John H.

doi:10.1016/j.bmcl.2011.04.149

Cited by 18 publications

(15 citation statements)

References 19 publications

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“…A novel PKR inhibitor was recently identified that can inhibit the enzyme within intact macrophages at mid-micromolar concentrations [33]. When applied to wild type macrophages, the inhibitor, N -(2(1 H -indol-3-yl)ethyl)-4-(2-methyl- 1H -indol-3-yl)pyrimin-2-amine (Figure 6A), partially phenocopied PKR deficiency in promoting nitrite release (Figure 6B) and suppressing IL10 release (Figure 6C) in response to IFN-gamma.…”

Section: Resultsmentioning

confidence: 99%

Improved Control of Tuberculosis and Activation of Macrophages in Mice Lacking Protein Kinase R

Koo²,

Jiang³

et al. 2012

PLoS ONE

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Host factors that microbial pathogens exploit for their propagation are potential targets for therapeuic countermeasures. No host enzyme has been identified whose genetic absence benefits the intact mammalian host in vivo during infection with Mycobacterium tuberculosis (Mtb), the leading cause of death from bacterial infection. Here, we report that the dsRNA-dependent protein kinase (PKR) is such an enzyme. PKR-deficient mice contained fewer viable Mtb and showed less pulmonary pathology than wild type mice. We identified two potential mechanisms for the protective effect of PKR deficiency: increased apoptosis of macrophages in response to Mtb and enhanced activation of macrophages in response to IFN-gamma. The restraining effect of PKR on macrophage activation was explained by its mediation of a previously unrecognized ability of IFN-gamma to induce low levels of the macrophage deactivating factor interleukin 10 (IL10). These observations suggest that PKR inhibitors may prove useful as an adjunctive treatment for tuberculosis.

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Section: Resultsmentioning

confidence: 99%

Improved Control of Tuberculosis and Activation of Macrophages in Mice Lacking Protein Kinase R

Koo²,

Jiang³

et al. 2012

PLoS ONE

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“…Further dilutions were made in sterile 1x PBS immediately prior to cell treatments. For the in vitro experiments, C16 was used at different concentrations based on previously published data (i.e., 0.05, 0.1, 0.2, 0.5, and 1.0 μM), 39 - 41 whereas C51 was used at 2.0, 10, and 30 μM 36 . In DMSO-treated cells, the solvent percentage corresponded to its concentration in the diluted active compounds (0.0005, 0.001, 0.002, 0.005, 0.01, and 0.3%).…”

Section: Methodsmentioning

confidence: 99%

“…Herein, we describe the use of two small molecule ATP site-directed kinase inhibitors: the imidazolo-oxindole inhibitor C16 (6,8-Dihydro-8-[1H-imidazol-5-ylmethylene]-7H-pyrrolo [2,3-g]benzothiazol-7-one) 35 and the pyrimidine-based inhibitor C51 (N-[2-{1H-indol-3-yl}ethyl]-4-[2-methyl-1H-indol-3-yl] pyrimidin-2-amine) 36 . Previous studies have identified these two compounds as protein kinase R (PKR) inhibitors; however, these chemicals can also exert activity against other targets because ATP-binding sites are abundant in the kinome.…”

Section: Introductionmentioning

confidence: 99%

Small molecule kinase inhibitors alleviate different molecular features of myotonic dystrophy type 1

et al. 2014

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Expandable (CTG)n repeats in the 3′ UTR of the DMPK gene are a cause of myotonic dystrophy type 1 (DM1), which leads to a toxic RNA gain-of-function disease. Mutant RNAs with expanded CUG repeats are retained in the nucleus and aggregate in discrete inclusions. These foci sequester splicing factors of the MBNL family and trigger upregulation of the CUGBP family of proteins resulting in the mis-splicing of their target transcripts. To date, many efforts to develop novel therapeutic strategies have been focused on disrupting the toxic nuclear foci and correcting aberrant alternative splicing via targeting mutant CUG repeats RNA; however, no effective treatment for DM1 is currently available. Herein, we present results of culturing of human DM1 myoblasts and fibroblasts with two small-molecule ATP-binding site-specific kinase inhibitors, C16 and C51, which resulted in the alleviation of the dominant-negative effects of CUG repeat expansion. Reversal of the DM1 molecular phenotype includes a reduction of the size and number of foci containing expanded CUG repeat transcripts, decreased steady-state levels of CUGBP1 protein, and consequent improvement of the aberrant alternative splicing of several pre-mRNAs misregulated in DM1.

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“…However, there are no published reports on the anticancer properties of this compound. More recently, a collection of 80 known kinase inhibitors were screened against recombinant full-length human PKR and these data were used to generate a predictive model of PKR inhibition [62]. The model was then used to carry out an in silico screen of~5 million commercially available compounds.…”

Section: Inhibitors Of Pkrmentioning

confidence: 99%

Targeting the ATF4 pathway in cancer therapy

Singleton

Harris

2012

Expert Opinion on Therapeutic Targets

119

112

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Identification of new inhibitors of protein kinase R guided by statistical modeling

Cited by 18 publications

References 19 publications

Improved Control of Tuberculosis and Activation of Macrophages in Mice Lacking Protein Kinase R

Improved Control of Tuberculosis and Activation of Macrophages in Mice Lacking Protein Kinase R

Small molecule kinase inhibitors alleviate different molecular features of myotonic dystrophy type 1

Targeting the ATF4 pathway in cancer therapy

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