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
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.
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.
