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Structure-Based Drug Discovery Targeting the Bromodomains of TAF1 (TFIID subunit 1)
EP25522
Poster Title: Structure-Based Drug Discovery Targeting the Bromodomains of TAF1 (TFIID subunit 1)
Submitted on 09 Feb 2017
Author(s): Md Rezaul Karim, Jinyi Zhu, Ernst Schonbrunn
Affiliations: University of South Florida; Moffitt Cancer Center
Poster Views: 688
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Poster Information
Abstract: TAF1 (TBP associated factor 1), the major component of general transcription factors that nucleates the formation of pre-initiation complex (PIC) for transcription machinery, plays important role in transcriptional dysregulation in malignant transformation resulting into cancer as well as in other diseases. With the current anti-cancer drugs, regulation of this dysregulated transcription is not achieved due to lack of targetable options on the surface of this large molecule. To close the gap, current research introduces a new approach to target the TAF1 through its epigenetic reader domains, the bromodomains. The long-term goal of this research project is to develop a potent and selective bromodomain inhibitor of TAF1 to modulate aberrant gene transcription in cancer by screening chemical libraries through differential scanning fluorimetry (DSF) assay in a HTS campaign, which will be validated and characterized by X-ray crystallography coupled with isothermal titration calorimetry (ITC) to develop novel chemical probes. Collectively, using these array of screening and validation experiments a drug candidate will be developed to be added in the regimen of cancer therapeutics.Summary: Recent advancement in research indicates that targeting epigenetic processes will be the next revolutionary approach to develop therapeutic agents against cancer. In this proposal, we will discover and characterize new small molecule inhibitors for a major epigenetic protein involved in malignancy.References: References
1 Filippakopoulos, P. et al. Selective inhibition of BET bromodomains. Nature 468, 1067-1073, doi:10.1038/nature09504 (2010).
2 Roy, A. L. & Singer, D. S. Core promoters in transcription: old problem, new insights. Trends Biochem Sci 40, 165-171,
3 Thomas, M. C. & Chiang, C. M. The general transcription machinery and general cofactors. Crit Rev Biochem Mol Biol 41, 105-178,
4 Buratowski, S., Hahn, S., Guarente, L. & Sharp, P. A. Five intermediate complexes in transcription initiation by RNA polymerase II. Cell 56, 549-561 (1989).
5 Wassarman, D. A. & Sauer, F. TAFII250. a transcription toolbox 114, 2895-2902 (2001).
6 Hong, B., Le Gallo, M. & Bell, D. W. The Mutational Landscape of Endometrial Cancer. Curr Opin Genet Dev 30, 25-31,
7 Zhao, S. et al. Landscape of somatic single-nucleotide and copy-number mutations in uterine serous carcinoma. Proc Natl Acad Sci U S A 110, 2916-2921,
8 Wada, C., Kasai, K., Kameya, T. & Ohtani, H. A general tr
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