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. 2017 May 15;27(10):2225-2233.
doi: 10.1016/j.bmcl.2017.02.057. Epub 2017 Feb 24.

Methylpyrrole inhibitors of BET bromodomains

Lisa A Hasvold  1 , George S Sheppard  2 , Le Wang  1 , Steven D Fidanze  1 , Dachun Liu  1 , John K Pratt  1 , Robert A Mantei  1 , Carol K Wada  1 , Robbert Hubbard  1 , Yu Shen  1 , Xiaoyu Lin  1 , Xiaoli Huang  1 , Scott E Warder  1 , Denise Wilcox  1 , Leiming Li  1 , F Greg Buchanan  1 , Lauren Smithee  1 , Daniel H Albert  1 , Terrance J Magoc  1 , Chang H Park  1 , Andrew M Petros  1 , Sanjay C Panchal  1 , Chaohong Sun  1 , Peter Kovar  1 , Nirupama B Soni  1 , Steven W Elmore  1 , Warren M Kati  1 , Keith F McDaniel  1
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Methylpyrrole inhibitors of BET bromodomains

Lisa A Hasvold et al. Bioorg Med Chem Lett. .

Abstract

An NMR fragment screen for binders to the bromodomains of BRD4 identified 2-methyl-3-ketopyrroles 1 and 2. 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.

Keywords: BET proteins; Bromodomain; Fragment screening.

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