Limits...
Exploring the utility of organo-polyoxometalate hybrids to inhibit SOX transcription factors.

Narasimhan K, Micoine K, Lacôte E, Thorimbert S, Cheung E, Hasenknopf B, Jauch R - Cell Regen (Lond) (2014)

Bottom Line: Polyoxometalates belonging to the Dawson structural class were found to be more potent inhibitors than the Keggin class.Further, organically modified Dawson polyoxometalates were found to be the most potent in inhibiting transcription factor DNA binding activity.The size of the polyoxometalates and its derivitization were found to be the key determinants of their potency.

View Article: PubMed Central - HTML - PubMed

Affiliation: Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto M5S 3E1, Canada ; Genome Institute of Singapore, 60 Biopolis Street, Buona Vista 138672, Singapore.

ABSTRACT

Background: SOX transcription factors constitute an attractive target class for intervention with small molecules as they play a prominent role in the field of regenerative biomedicine and cancer biology. However, rationally engineering specific inhibitors that interfere with transcription factor DNA interfaces continues to be a monumental challenge in the field of transcription factor chemical biology. Polyoxometalates (POMs) are inorganic compounds that were previously shown to target the high-mobility group (HMG) of SOX proteins at nanomolar concentrations. In continuation of this work, we carried out an assessment of the selectivity of a panel of newly synthesized organo-polyoxometalate hybrids in targeting different transcription factor families to enable the usage of polyoxometalates as specific SOX transcription factor drugs.

Results: The residual DNA-binding activities of 15 different transcription factors were measured after treatment with a panel of diverse polyoxometalates. Polyoxometalates belonging to the Dawson structural class were found to be more potent inhibitors than the Keggin class. Further, organically modified Dawson polyoxometalates were found to be the most potent in inhibiting transcription factor DNA binding activity. The size of the polyoxometalates and its derivitization were found to be the key determinants of their potency.

Conclusion: Polyoxometalates are highly potent, nanomolar range inhibitors of the DNA binding activity of the Sox-HMG family. However, binding assays involving a limited subset of structurally diverse polyoxometalates revealed a low selectivity profile against different transcription factor families. Further progress in achieving selectivity and deciphering structure-activity relationship of POMs require the identification of POM binding sites on transcription factors using elaborate approaches like X-ray crystallography and multidimensional NMR. In summary, our report reaffirms that transcription factors are challenging molecular architectures and that future polyoxometalate chemistry must consider further modification strategies, to address the substantial challenges involved in achieving target selectivity.

No MeSH data available.


Related in: MedlinePlus

A heatmap displaying the average residual DNA binding activities of 15 different TFs upon treatment with 125 nM of a panel of inhibitor compounds. The residual DNA binding activity is reported as an average of five independent experiments. Two-dimensional clustering of the residual DNA binding activities was carried out by hierarchical clustering analysis (Euclidean distance). (Red color indicates high inhibition, while yellow color indicates relatively lesser inhibition). Inhibitor compounds are color coded by their POM class. Inset shows typical inhibition profiles of representative TFs namely Sox17, REST and Pax6 upon treatment with Dawson POM K6 [P2Mo18O62] (D1Mo), measured by fluorescence anisotropy.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC4306199&req=5

Figure 2: A heatmap displaying the average residual DNA binding activities of 15 different TFs upon treatment with 125 nM of a panel of inhibitor compounds. The residual DNA binding activity is reported as an average of five independent experiments. Two-dimensional clustering of the residual DNA binding activities was carried out by hierarchical clustering analysis (Euclidean distance). (Red color indicates high inhibition, while yellow color indicates relatively lesser inhibition). Inhibitor compounds are color coded by their POM class. Inset shows typical inhibition profiles of representative TFs namely Sox17, REST and Pax6 upon treatment with Dawson POM K6 [P2Mo18O62] (D1Mo), measured by fluorescence anisotropy.

Mentions: In total, the residual DNA binding activities of 15 different TFs were estimated against a panel of inhibitors that could be broadly classified into “Keggin”, “Dawson” and “simpler polyanion” (metatungstate, sodium molybdate and decavanadate) types. The structures, compound acronyms and the chemical formulas of POMs employed in this study are given in Figure 1 and Table 1. The mean residual DNA binding activity of TFs from five independent experiments is displayed as a heatmap after hierarchical clustering analysis using the “R heatmap.2” package (Figure 2) [32].


Exploring the utility of organo-polyoxometalate hybrids to inhibit SOX transcription factors.

Narasimhan K, Micoine K, Lacôte E, Thorimbert S, Cheung E, Hasenknopf B, Jauch R - Cell Regen (Lond) (2014)

A heatmap displaying the average residual DNA binding activities of 15 different TFs upon treatment with 125 nM of a panel of inhibitor compounds. The residual DNA binding activity is reported as an average of five independent experiments. Two-dimensional clustering of the residual DNA binding activities was carried out by hierarchical clustering analysis (Euclidean distance). (Red color indicates high inhibition, while yellow color indicates relatively lesser inhibition). Inhibitor compounds are color coded by their POM class. Inset shows typical inhibition profiles of representative TFs namely Sox17, REST and Pax6 upon treatment with Dawson POM K6 [P2Mo18O62] (D1Mo), measured by fluorescence anisotropy.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4306199&req=5

Figure 2: A heatmap displaying the average residual DNA binding activities of 15 different TFs upon treatment with 125 nM of a panel of inhibitor compounds. The residual DNA binding activity is reported as an average of five independent experiments. Two-dimensional clustering of the residual DNA binding activities was carried out by hierarchical clustering analysis (Euclidean distance). (Red color indicates high inhibition, while yellow color indicates relatively lesser inhibition). Inhibitor compounds are color coded by their POM class. Inset shows typical inhibition profiles of representative TFs namely Sox17, REST and Pax6 upon treatment with Dawson POM K6 [P2Mo18O62] (D1Mo), measured by fluorescence anisotropy.
Mentions: In total, the residual DNA binding activities of 15 different TFs were estimated against a panel of inhibitors that could be broadly classified into “Keggin”, “Dawson” and “simpler polyanion” (metatungstate, sodium molybdate and decavanadate) types. The structures, compound acronyms and the chemical formulas of POMs employed in this study are given in Figure 1 and Table 1. The mean residual DNA binding activity of TFs from five independent experiments is displayed as a heatmap after hierarchical clustering analysis using the “R heatmap.2” package (Figure 2) [32].

Bottom Line: Polyoxometalates belonging to the Dawson structural class were found to be more potent inhibitors than the Keggin class.Further, organically modified Dawson polyoxometalates were found to be the most potent in inhibiting transcription factor DNA binding activity.The size of the polyoxometalates and its derivitization were found to be the key determinants of their potency.

View Article: PubMed Central - HTML - PubMed

Affiliation: Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto M5S 3E1, Canada ; Genome Institute of Singapore, 60 Biopolis Street, Buona Vista 138672, Singapore.

ABSTRACT

Background: SOX transcription factors constitute an attractive target class for intervention with small molecules as they play a prominent role in the field of regenerative biomedicine and cancer biology. However, rationally engineering specific inhibitors that interfere with transcription factor DNA interfaces continues to be a monumental challenge in the field of transcription factor chemical biology. Polyoxometalates (POMs) are inorganic compounds that were previously shown to target the high-mobility group (HMG) of SOX proteins at nanomolar concentrations. In continuation of this work, we carried out an assessment of the selectivity of a panel of newly synthesized organo-polyoxometalate hybrids in targeting different transcription factor families to enable the usage of polyoxometalates as specific SOX transcription factor drugs.

Results: The residual DNA-binding activities of 15 different transcription factors were measured after treatment with a panel of diverse polyoxometalates. Polyoxometalates belonging to the Dawson structural class were found to be more potent inhibitors than the Keggin class. Further, organically modified Dawson polyoxometalates were found to be the most potent in inhibiting transcription factor DNA binding activity. The size of the polyoxometalates and its derivitization were found to be the key determinants of their potency.

Conclusion: Polyoxometalates are highly potent, nanomolar range inhibitors of the DNA binding activity of the Sox-HMG family. However, binding assays involving a limited subset of structurally diverse polyoxometalates revealed a low selectivity profile against different transcription factor families. Further progress in achieving selectivity and deciphering structure-activity relationship of POMs require the identification of POM binding sites on transcription factors using elaborate approaches like X-ray crystallography and multidimensional NMR. In summary, our report reaffirms that transcription factors are challenging molecular architectures and that future polyoxometalate chemistry must consider further modification strategies, to address the substantial challenges involved in achieving target selectivity.

No MeSH data available.


Related in: MedlinePlus