Small-Molecule Inhibitors of the SOX18 Transcription Factor.
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.
Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
Frank
F
Fontaine
Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
Jeroen
J
Overman
Single Molecule Science, Lowy Cancer Research Centre, The University of New South Wales, Sydney, NSW 2031, Australia.
Mehdi
M
Moustaqil
Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
Sreeman
S
Mamidyala
Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
Angela
A
Salim
Laboratory for Structural Biochemistry, Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672, Singapore.
Kamesh
K
Narasimhan
Laboratory for Structural Biochemistry, Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672, Singapore.
Nina
N
Prokoph
Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
Avril A B
AAB
Robertson
Protein Expression Facility, The University of Queensland, St. Lucia, QLD 4072, Australia.
Linda
L
Lua
Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
Kirill
K
Alexandrov
Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
Peter
P
Koopman
Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
Robert J
RJ
Capon
Single Molecule Science, Lowy Cancer Research Centre, The University of New South Wales, Sydney, NSW 2031, Australia.
Emma
E
Sierecki
Single Molecule Science, Lowy Cancer Research Centre, The University of New South Wales, Sydney, NSW 2031, Australia.
Yann
Y
Gambin
Genome Regulation Laboratory, Drug Discovery Pipeline, Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong 510530, China; Guangzhou Medical University, Guangzhou 511436, China.
Ralf
R
Jauch
Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
Matthew A
MA
Cooper
Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia. Electronic address: j.zuegg@imb.uq.edu.au.
Johannes
J
Zuegg
Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia. Electronic address: m.francois@imb.uq.edu.au.
Mathias
M
Francois
D000818:Animals; D001665:Binding Sites; D001688:Biological Products / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D019556:COS Cells; D002522:Chlorocebus aethiops; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D017930:Genes, Reporter; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000737:chemistry / Q000378:metabolism; D020128:Inhibitory Concentration 50; D051379:Mice; D009690:Nucleic Acid Conformation; D011485:Protein Binding; D060066:Protein Interaction Maps; D017434:Protein Structure, Tertiary; D055760:SOXF Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020156:Salicylic Acid / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation / Q000187:drug effects
D001688:Biological Products; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; C497570:RBPJ protein, human; D055760:SOXF Transcription Factors; D054852:Small Molecule Libraries; D004247:DNA; D020156:Salicylic Acid
SOX transcription factor; protein-DNA interaction; protein-protein interaction; salicylate; small-molecule