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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

The panel of polyoxometalates used in this study. Compound acronyms and the chemical formulas are as provided in Table 1.
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Figure 1: The panel of polyoxometalates used in this study. Compound acronyms and the chemical formulas are as provided in Table 1.

Mentions: Transcription factors (TFs) with critical functions in cancer and stem-cell biology are desirable targets for small molecule inhibition [1,2]. In particular, members of the SOX TF family were reported to drive cancer progression [3,4]. However, chemical inhibitors of SOX proteins that would have great potential to counteract oncogenesis are presently not available. Some of the best selling drugs approved by the FDA (Food and drug administration) are in fact known to target TFs [5]. However, those drugs do not bind the DNA binding domains (DBDs) of TFs because of their highly electrostatic nature, the lack of binding pockets, and the structural dynamics of TFs in the absence of DNA [6]. We hypothesized that the negatively charged Polyoxometalates (POMs) provide a suitable scaffold for targeting DBDs [7]. POMs are nanometer sized inorganic oxyanions comprising transition metals belonging to Group 5 and 6 of the periodic table in their highest oxidation states [8]. The metals are held together by oxygen atoms and often enclose one or more central heteroatoms like phosphorus or silicon. Some common structural POM families of importance in the field of biomedicine are the Keggin [XM12O40]n-, and the Dawson structure [X2M18O62]n– where M is the transition metal atom (typically tungsten or molybdenum), X is the heteroatom (typically phosphorous) and n is the number of ionic charges (Figure 1) [8].


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)

The panel of polyoxometalates used in this study. Compound acronyms and the chemical formulas are as provided in Table 1.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: The panel of polyoxometalates used in this study. Compound acronyms and the chemical formulas are as provided in Table 1.
Mentions: Transcription factors (TFs) with critical functions in cancer and stem-cell biology are desirable targets for small molecule inhibition [1,2]. In particular, members of the SOX TF family were reported to drive cancer progression [3,4]. However, chemical inhibitors of SOX proteins that would have great potential to counteract oncogenesis are presently not available. Some of the best selling drugs approved by the FDA (Food and drug administration) are in fact known to target TFs [5]. However, those drugs do not bind the DNA binding domains (DBDs) of TFs because of their highly electrostatic nature, the lack of binding pockets, and the structural dynamics of TFs in the absence of DNA [6]. We hypothesized that the negatively charged Polyoxometalates (POMs) provide a suitable scaffold for targeting DBDs [7]. POMs are nanometer sized inorganic oxyanions comprising transition metals belonging to Group 5 and 6 of the periodic table in their highest oxidation states [8]. The metals are held together by oxygen atoms and often enclose one or more central heteroatoms like phosphorus or silicon. Some common structural POM families of importance in the field of biomedicine are the Keggin [XM12O40]n-, and the Dawson structure [X2M18O62]n– where M is the transition metal atom (typically tungsten or molybdenum), X is the heteroatom (typically phosphorous) and n is the number of ionic charges (Figure 1) [8].

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