期刊
CELL CHEMICAL BIOLOGY
卷 24, 期 3, 页码 346-359出版社
CELL PRESS
DOI: 10.1016/j.chembiol.2017.01.003
关键词
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资金
- National Health and Medical Research Council of Australia (NHMRC) Career Development Fellowship [APP1111169]
- NHMRC Senior Principal Research Fellowships [APP1059006]
- Australia Fellowship [AF51105]
- NHMRC [APP1025082, APP1048242, APP1107643]
- Cancer Council Queensland [1008392, 1048237, 1107631]
- Australian Research Council [FT110100478, DP130102396, DP120101423]
- C4D (IMB, The University of Queensland)
- MOST China-EU Science and Technology Cooperation Program [2013DFE33080]
- National Natural Science Foundation of China [31471238]
- 100 talent award of the Chinese Academy of Sciences
- Australian Research Council [FT110100478] Funding Source: Australian Research Council
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.
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