| Literature DB >> 27115555 |
Brian S Gerstenberger1, John D Trzupek1, Cynthia Tallant2,3, Oleg Fedorov2,3, Panagis Filippakopoulos2,4, Paul E Brennan2,3, Vita Fedele2,3, Sarah Martin2,3, Sarah Picaud2,3, Catherine Rogers2,3, Mihir Parikh5, Alexandria Taylor5, Brian Samas6, Alison O'Mahony7, Ellen Berg7, Gabriel Pallares8, Adam D Torrey8, Daniel K Treiber8, Ivan J Samardjiev9, Brian T Nasipak10, Teresita Padilla-Benavides10, Qiong Wu10, Anthony N Imbalzano10, Jeffrey A Nickerson10, Mark E Bunnage1, Susanne Müller2,3, Stefan Knapp2,3,11, Dafydd R Owen1.
Abstract
The acetyl post-translational modification of chromatin at selected histone lysine residues is interpreted by an acetyl-lysine specific interaction with bromodomain reader modules. Here we report the discovery of the potent, acetyl-lysine-competitive, and cell active inhibitor PFI-3 that binds to certain family VIII bromodomains while displaying significant, broader bromodomain family selectivity. The high specificity of PFI-3 for family VIII was achieved through a novel bromodomain binding mode of a phenolic headgroup that led to the unusual displacement of water molecules that are generally retained by most other bromodomain inhibitors reported to date. The medicinal chemistry program that led to PFI-3 from an initial fragment screening hit is described in detail, and additional analogues with differing family VIII bromodomain selectivity profiles are also reported. We also describe the full pharmacological characterization of PFI-3 as a chemical probe, along with phenotypic data on adipocyte and myoblast cell differentiation assays.Entities:
Mesh：
Substances：
Year: 2016 PMID： 27115555 PMCID： PMC5034155 DOI： 10.1021/acs.jmedchem.6b00012
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446