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Download fileIdentification of a Chemical Probe for Family VIII Bromodomains through Optimization of a Fragment Hit
journal contribution
posted on 26.04.2016, 00:00 authored by Brian
S. Gerstenberger, John D. Trzupek, Cynthia Tallant, Oleg Fedorov, Panagis Filippakopoulos, Paul E. Brennan, Vita Fedele, Sarah Martin, Sarah Picaud, Catherine Rogers, Mihir Parikh, Alexandria Taylor, Brian Samas, Alison O’Mahony, Ellen Berg, Gabriel Pallares, Adam D. Torrey, Daniel K. Treiber, Ivan J. Samardjiev, Brian T. Nasipak, Teresita Padilla-Benavides, Qiong Wu, Anthony N. Imbalzano, Jeffrey A. Nickerson, Mark
E. Bunnage, Susanne Müller, Stefan Knapp, Dafydd R. OwenThe 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.
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Keywords
novel bromodomain binding modefamily VIIIphenotypic datawater moleculesbromodomain inhibitorsfamily VIII bromodomainsmyoblast cell differentiation assayschemistry programChemical Probefragment screeningfamily VIII bromodomain selectivity profilesPFIchemical probebromodomain reader modulesphenolic headgroupFamily VIII Bromodomainsbromodomain family selectivityhistone lysine residues