title: Exploring the utility of organo-polyoxometalate hybrids to inhibit SOX transcription factors.
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.
  
  
  CONCLUSIONS
  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.
authors: 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.
authors: Kamesh
authors: K
authors: Narasimhan
authors: Sorbonne Universités, UPMC Univ Paris 06, Institut Parisien de Chimie Moléculaire, UMR 8232, 4 Place Jussieu, 75005 Paris, France.
authors: Kevin
authors: K
authors: Micoine
authors: Sorbonne Universités, UPMC Univ Paris 06, Institut Parisien de Chimie Moléculaire, UMR 8232, 4 Place Jussieu, 75005 Paris, France.
authors: Emmanuel
authors: E
authors: Lacôte
authors: Sorbonne Universités, UPMC Univ Paris 06, Institut Parisien de Chimie Moléculaire, UMR 8232, 4 Place Jussieu, 75005 Paris, France.
authors: Serge
authors: S
authors: Thorimbert
authors: Genome Institute of Singapore, 60 Biopolis Street, Buona Vista 138672, Singapore ; Faculty of Health Sciences, University of Macau, Av. Padre Tomas Pereira, Taipa, Macau, China.
authors: Edwin
authors: E
authors: Cheung
authors: Sorbonne Universités, UPMC Univ Paris 06, Institut Parisien de Chimie Moléculaire, UMR 8232, 4 Place Jussieu, 75005 Paris, France ; CNRS, Institut Parisien de Chimie Moléculaire, UMR 8232, 4 Place Jussieu, Paris, 75005, France.
authors: Bernold
authors: B
authors: Hasenknopf
authors: Genome Institute of Singapore, 60 Biopolis Street, Buona Vista 138672, Singapore ; Genome Regulation Laboratory, Drug Development Pipeline, Guangzhou Institutes of Biomedicine, 190 Kai Yuan Avenue, Science Park, 510530 Guangzhou, China.
authors: Ralf
authors: R
authors: Jauch