Small-molecule inhibitors of the SOX18 transcription factor

Fontaine, Frank, Overman, Jeroen, Moustaqil, Mehdi, Mamidyala, Sreeman, Salim, Angela, Narasimhan, Kamesh, Prokoph, Nina, Robertson, Avril A. B., Lua, Linda, Alexandrov, Kirill, Koopman, Peter, Capon, Robert J., Sierecki, Emma, Gambin, Yann, Jauch, Ralf, Cooper, Matthew A., Zuegg, Johannes and Francois, Mathias (2017) Small-molecule inhibitors of the SOX18 transcription factor. Chemistry Chemical Biology, 24 3: 346-359. doi:10.1016/j.chembiol.2017.01.003

Author Fontaine, Frank
Overman, Jeroen
Moustaqil, Mehdi
Mamidyala, Sreeman
Salim, Angela
Narasimhan, Kamesh
Prokoph, Nina
Robertson, Avril A. B.
Lua, Linda
Alexandrov, Kirill
Koopman, Peter
Capon, Robert J.
Sierecki, Emma
Gambin, Yann
Jauch, Ralf
Cooper, Matthew A.
Zuegg, Johannes
Francois, Mathias
Title Small-molecule inhibitors of the SOX18 transcription factor
Journal name Chemistry Chemical Biology
ISSN 2451-9448
Publication date 2017-02-02
Year available 2017
Sub-type Article (original research)
DOI 10.1016/j.chembiol.2017.01.003
Open Access Status Not yet assessed
Volume 24
Issue 3
Start page 346
End page 359
Total pages 14
Place of publication Cambridge, MA, United States
Publisher Cell Press
Language eng
Subject 1303 Biochemistry
1313 Molecular Medicine
1312 Molecular Biology
3004 Pharmacology
3002 Drug Discovery
1308 Clinical Biochemistry
Abstract Pharmacological modulation of transcription factors (TFs) has only met little success over the past four decades. This is mostly due to standard drug discovery approaches centered on blocking protein/DNA binding or interfering with post-translational modifications. Recent advances in the field of TF biology have revealed a central role of protein-protein interaction in their mode of action. In an attempt to modulate the activity of SOX18 TF, a known regulator of vascular growth in development and disease, we screened a marine extract library for potential small-molecule inhibitors. We identified two compounds, which inspired a series of synthetic SOX18 inhibitors, able to interfere with the SOX18 HMG DNA-binding domain, and to disrupt HMG-dependent protein-protein interaction with RBPJ. These compounds also perturbed SOX18 transcriptional activity in a cell-based reporter gene system. This approach may prove useful in developing a new class of anti-angiogenic compounds based on the inhibition of TF activity. Fontaine et al. describe a novel avenue for manipulating SOX18 transcription factor activity using small-molecule inhibitors. This approach shows that the inhibitors block transcriptional activation by disrupting protein-protein interaction.
Keyword Protein-DNA interaction
Protein-protein interaction
SOX transcription factor
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID APP1111169
Institutional Status UQ

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