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Methylpyrrole inhibitors of BET bromodomains.

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.

Bioorg Med Chem Lett ; 27(10): 2225-2233, 2017 05 15.

Article in English | MEDLINE | ID: mdl-28268136

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.

Subject(s)

Antineoplastic Agents/chemistry , Nuclear Proteins/antagonists & inhibitors , Pyrroles/chemistry , Transcription Factors/antagonists & inhibitors , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Binding Sites , Cell Line, Tumor , Cell Proliferation/drug effects , Crystallography, X-Ray , Drug Design , Half-Life , Humans , Mice , Molecular Dynamics Simulation , Multiple Myeloma/drug therapy , Nuclear Proteins/metabolism , Pyrroles/chemical synthesis , Pyrroles/pharmacokinetics , Pyrroles/therapeutic use , Structure-Activity Relationship , Transcription Factors/metabolism , Transplantation, Heterologous

ABSTRACT

Subject(s)

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