Identification of a polyoxometalate inhibitor of the DNA binding activity of sox2

Kamesh Narasimhan, Shubhadra Pillay, Nor Rizal Bin Ahmad, Zsolt Bikadi, Eszter Hazai, Li Yan, Prasanna Kolatkar, Konstantin Pervushin, Ralf Jauch

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Abstract

Aberrant expression of transcription factors is a frequent cause of disease, yet drugs that modulate transcription factor protein-DNA interactions are presently unavailable. To this end, the chemical tractability of the DNA binding domain of the stem cell inducer and oncogene Sox2 was explored in a high-throughput fluorescence anisotropy screen. The screening revealed a Dawson polyoxometalate (K 6[P 2Mo 18O 62]) as a direct and nanomolar inhibitor of the DNA binding activity of Sox2. The Dawson polyoxometalate (Dawson-POM) was found to be selective for Sox2 and related Sox-HMG family members when compared to unrelated paired and zinc finger DNA binding domains. [ 15N, 1H]-Transverse relaxation optimized spectroscopy (TROSY) experiments coupled with docking studies suggest an interaction site of the POM on the Sox2 surface that enabled the rationalization of its inhibitory activity. The unconventional molecular scaffold of the Dawson-POM and its inhibitory mode provides strategies for the development of drugs that modulate transcription factors.

Original languageEnglish
Pages (from-to)573-581
Number of pages9
JournalACS Chemical Biology
Volume6
Issue number6
DOIs
Publication statusPublished - 17 Jun 2011
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

Cite this

Narasimhan, K., Pillay, S., Bin Ahmad, N. R., Bikadi, Z., Hazai, E., Yan, L., Kolatkar, P., Pervushin, K., & Jauch, R. (2011). Identification of a polyoxometalate inhibitor of the DNA binding activity of sox2. ACS Chemical Biology, 6(6), 573-581. https://doi.org/10.1021/cb100432x