DISCOVERY, STRUCTURE-FUNCTION CHARACTERIZATION AND ASSESSMENT OF POLYOXOMETALATES AS MODULATORS OF THE DNA BINDING ACTIVITY OF THE SOX-HMG FAMILY OF TRANSCRIPTION FACTORS

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 (K6[Mo18O62P2]) as a direct and nanomolar inhibitor of the DNA binding activity of Sox2. [15N,1H]-Transverse relaxation optimized spectroscopy (TROSY) experiments coupled with docking studies suggest an interaction site of the Dawson polyoxometalate(K6[P2Mo18O62]) on the Sox2 surface that enabled the rationalization of its inhibitory activity. Detailed investigation on a panel of different transcription factors against an expanded set of various polyoxometalates revealed that the Keggin and Dawson class of polyoxometalates exhibit a marked dichotomy in their selectivity and inhibition potential of the Sox-HMG family of transcription factors. Dawson polyoxometalates modified with organic moieties were found to invariably amplify the inhibitory potency of the pristine ¿Dawson¿ scaffold against Sox-HMG members, while a commensurate change in selective discrimination of the HMG family members could not be observed. The functionalization effect of the Dawson scaffold in inhibiting the Sox-HMG family merits investigation in the future. Taken in its entirety, the polyoxometalates have expanded the repertoire of molecular scaffolds that render transcription factors chemically tractable and provide strategies for the development of drugs that modulate transcription factors.