Profiles of experimental affinity data of the 20 drugs, among 4,819, hitting more than 5 targets found solely in tumor selective compounds.

<p>Only affinities above 1 µM are considered. Color coding reflects pAffinity ranges: white 6–7; light grey 7–8; dark grey 8–9; black >9. Color codes for targets refer to HDACs (yellow), kinases (orange), and other (green).</p

Distribution of oncogene probabilities for the proteins predicted uniquely for compounds selective to HCT116 (black) and MRC-5 (light grey) and the proteins found in both selective sets (dark grey).

<p>NA collects all proteins for which oncogene probabilities were not available from CGPrio <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0035582#pone.0035582-Furney1" target="_blank">[34]</a>.</p

Figure 4

<p> <b>a) Venn diagram of the protein targets predicted for the selective cytotoxic compounds to HCT116 and MRC-5 cell lines; b) distribution across protein families of the 115 targets predicted to interact uniquely with selective cytotoxic compounds to tumor cells; and c) distribution across enzyme classes of the 67 enzymes present in the list of 115 putative cancer targets.</b></p

Figure 2

<p> <b>a) Correlation of two independent viability values determined for the same compound and b) distribution of viability values for the chemical library of 30,000 compounds.</b></p

Figure 3

<p> <b>a) Distribution of the cytotoxicity (IC50 values) of the selected compounds on HCT116 and MRC5 cells and b) distribution of the selective cytotoxicity against HCT116. NT means “non toxic”.</b></p

List of 42 proteins with OncoScore >0.7 among the 115 proteins identified by the DIVISS approach.

<p>The OncoScore is the oncogene probability calculated from CGPrio <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0035582#pone.0035582-Furney1" target="_blank">[34]</a>.The arrows next to the gene name mark the set of 10 proteins from this list that are known to be significantly altered (corrected p-value <0.05) in terms of up- or down-regulation in colon cancer, as extracted from the IntOGen platform <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0035582#pone.0035582-Gundem1" target="_blank">[33]</a>.</p

Schematic flowchart of the DIVISS approach applied in this work leading to the identification of 115 proteins of potential relevance to cancer.

<p>Schematic flowchart of the DIVISS approach applied in this work leading to the identification of 115 proteins of potential relevance to cancer.</p

Image5.pdf

<p>The objective of our present study is to develop novel inhibitors for MMP-2 for acute cardioprotection. In a series of pilot studies, novel substituted carboxylic acid derivatives were synthesized based on imidazole and thiazole scaffolds and then tested in a screeening cascade for MMP inhibition. We found that the MMP-inhibiting effects of imidazole and thiazole carboxylic acid-based compounds are superior in efficacy in comparison to the conventional hydroxamic acid derivatives of the same molecules. Based on these results, a 568-membered focused library of imidazole and thiazole compounds was generated in silico and then the library members were docked to the 3D model of MMP-2 followed by an in vitro medium throughput screening (MTS) based on a fluorescent assay employing MMP-2 catalytic domain. Altogether 45 compounds showed a docking score of >70, from which 30 compounds were successfully synthesized. Based on the MMP-2 inhibitory tests using gelatin zymography, 7 compounds were then selected and tested in neonatal rat cardiac myocytes subjected to simulated I/R injury. Six compounds showed significant cardio-cytoprotecion and the most effective compound (MMPI-1154) significantly decreased infarct size when applied at 1 μM in an ex vivo model for acute myocardial infarction. This is the first demonstration that imidazole and thiazole carboxylic acid-based compounds are more efficacious MMP-2 inhibitor than their hydroxamic acid derivatives. MMPI-1154 is a promising novel cardio-cytoprotective imidazole-carboxylic acid MMP-2 inhibitor lead candidate for the treatment of acute myocardial infarction.</p

Image1.pdf

<p>The objective of our present study is to develop novel inhibitors for MMP-2 for acute cardioprotection. In a series of pilot studies, novel substituted carboxylic acid derivatives were synthesized based on imidazole and thiazole scaffolds and then tested in a screeening cascade for MMP inhibition. We found that the MMP-inhibiting effects of imidazole and thiazole carboxylic acid-based compounds are superior in efficacy in comparison to the conventional hydroxamic acid derivatives of the same molecules. Based on these results, a 568-membered focused library of imidazole and thiazole compounds was generated in silico and then the library members were docked to the 3D model of MMP-2 followed by an in vitro medium throughput screening (MTS) based on a fluorescent assay employing MMP-2 catalytic domain. Altogether 45 compounds showed a docking score of >70, from which 30 compounds were successfully synthesized. Based on the MMP-2 inhibitory tests using gelatin zymography, 7 compounds were then selected and tested in neonatal rat cardiac myocytes subjected to simulated I/R injury. Six compounds showed significant cardio-cytoprotecion and the most effective compound (MMPI-1154) significantly decreased infarct size when applied at 1 μM in an ex vivo model for acute myocardial infarction. This is the first demonstration that imidazole and thiazole carboxylic acid-based compounds are more efficacious MMP-2 inhibitor than their hydroxamic acid derivatives. MMPI-1154 is a promising novel cardio-cytoprotective imidazole-carboxylic acid MMP-2 inhibitor lead candidate for the treatment of acute myocardial infarction.</p

Image3.pdf

<p>The objective of our present study is to develop novel inhibitors for MMP-2 for acute cardioprotection. In a series of pilot studies, novel substituted carboxylic acid derivatives were synthesized based on imidazole and thiazole scaffolds and then tested in a screeening cascade for MMP inhibition. We found that the MMP-inhibiting effects of imidazole and thiazole carboxylic acid-based compounds are superior in efficacy in comparison to the conventional hydroxamic acid derivatives of the same molecules. Based on these results, a 568-membered focused library of imidazole and thiazole compounds was generated in silico and then the library members were docked to the 3D model of MMP-2 followed by an in vitro medium throughput screening (MTS) based on a fluorescent assay employing MMP-2 catalytic domain. Altogether 45 compounds showed a docking score of >70, from which 30 compounds were successfully synthesized. Based on the MMP-2 inhibitory tests using gelatin zymography, 7 compounds were then selected and tested in neonatal rat cardiac myocytes subjected to simulated I/R injury. Six compounds showed significant cardio-cytoprotecion and the most effective compound (MMPI-1154) significantly decreased infarct size when applied at 1 μM in an ex vivo model for acute myocardial infarction. This is the first demonstration that imidazole and thiazole carboxylic acid-based compounds are more efficacious MMP-2 inhibitor than their hydroxamic acid derivatives. MMPI-1154 is a promising novel cardio-cytoprotective imidazole-carboxylic acid MMP-2 inhibitor lead candidate for the treatment of acute myocardial infarction.</p