TY - JOUR
T1 - Identification of a polyoxometalate inhibitor of the DNA binding activity of sox2
AU - Narasimhan, Kamesh
AU - Pillay, Shubhadra
AU - Bin Ahmad, Nor Rizal
AU - Bikadi, Zsolt
AU - Hazai, Eszter
AU - Yan, Li
AU - Kolatkar, Prasanna R.
AU - Pervushin, Konstantin
AU - Jauch, Ralf
PY - 2011/6/17
Y1 - 2011/6/17
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/79961094533
U2 - 10.1021/cb100432x
DO - 10.1021/cb100432x
M3 - Article
C2 - 21344919
AN - SCOPUS:79961094533
SN - 1554-8929
VL - 6
SP - 573
EP - 581
JO - ACS Chemical Biology
JF - ACS Chemical Biology
IS - 6
ER -