Small-Molecule Inhibitors of the SOX18 Transcription Factor. Issue 3 (16th March 2017)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: Cell chemical biology. Volume 24:Issue 3(2017)
• Page Start: 346
• Page End: 359
• Publication Date: 2017-03-16
• Subjects: SOX transcription factor -- protein-DNA interaction -- protein-protein interaction -- small-molecule -- salicylate; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2017.01.003
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: 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. Highlights: Novel small-moleculeSm4 inhibits SOX18 protein-protein interaction Transcription factor SOX18 interacts with Notch effector RBPJ Different small molecules inhibit distinct SOX18 protein-protein interactions SOX18-RBPJ interaction, mediated by HMG domain, is modulated by small-moleculeSm4 Abstract : 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.