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Synfacts 2014; 10(1): 0010
DOI: 10.1055/s-0033-1340327
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Epigenetic Regulator I-BET762 (GSK525762)

Contributor(s):
Philip Kocienski
Mirguet O, * Parr N. * et al. GlaxoSmithKline R&D, Villebon-sur-Yvette, France and Stevenage, UK
Discovery of Epigenetic Regulator I-BET762: Lead Optimization to Afford a Clinical Candidate Inhibitor of the BET Bromodomains.

J. Med. Chem. 2013;
56: 7501-7515
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Further Information

Publication History

Publication Date:
13 December 2013 (online)

 
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Key words

I-BET762 - GSK525762 - 1,4-benzodiazepines - 1,2,4-triazoles

Significance

I-BET762 (GSK525762) has entered phase I/II clinical trials for the treatment of the aggressive NUT midline carcinoma and other cancers. It disrupts the function of the bromo­domain and extra-terminal domain (BET) family of proteins. The synthesis depicted features the construction of the 1,4-benzodiazepine skeleton with incorporation of an (S)-aspartic acid moiety.


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Comment

For a synthesis of benzophenone A, see: C.-w. Chung et al. J. Med. Chem. 2011, 54, 3827. The easy epimerization of the stereogenic center that occurs in the thionation reaction (B → C) was suppressed by conducting the reaction in the presence of sodium carbonate. The (R)-enantiomer is biologically inactive as a BET inhibitor.


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