Methylpyrrole inhibitors of BET bromodomains. Issue 10 (15th May 2017)

• Record Type: Journal Article
• Authors: Hasvold, Lisa A.; Sheppard, George S.; Wang, Le; Fidanze, Steven D.; Liu, Dachun; Pratt, John K.; Mantei, Robert A.; Wada, Carol K.; Hubbard, Robbert; Shen, Yu; Lin, Xiaoyu; Huang, Xiaoli; Warder, Scott E.; Wilcox, Denise; Li, Leiming; Buchanan, F. Greg; Smithee, Lauren; Albert, Daniel H.; Magoc, Terrance J.; Park, Chang H.; Petros, Andrew M.; Panchal, Sanjay C.; Sun, Chaohong; Kovar, Peter; Soni, Nirupama B.; Elmore, Steven W.; Kati, Warren M.; McDaniel, Keith F.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 27:Issue 10(2017)
• Page Start: 2225
• Page End: 2233
• Publication Date: 2017-05-15
• Subjects: BET proteins -- Bromodomain -- Fragment screening; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2017.02.057
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: An NMR fragment screen for binders to the bromodomains of BRD4 identified 2-methyl-3-ketopyrroles1 and2 . Elaboration of these fragments guided by structure-based design provided lead molecules with significant activity in a mouse tumor model. Further modifications to the methylpyrrole core provided compounds with improved properties and enhanced activity in a mouse model of multiple myeloma.