Identification of a Chemical Probe for Family VIII Bromodomains through Optimization of a Fragment Hit. Gerstenberger, B., S., Trzupek, J., D., Tallant, C., Fedorov, O., Filippakopoulos, P., Brennan, P., E., Fedele, V., Martin, S., Picaud, S., Rogers, C., Parikh, M., Taylor, A., Samas, B., O'Mahony, A., Berg, E., Pallares, G., Torrey, A., D., Treiber, D., K., Samardjiev, I., J., Nasipak, B., T., Padilla-Benavides, T., Wu, Q., Imbalzano, A., N., Nickerson, J., A., Bunnage, M., E., Müller, S., Knapp, S., & Owen, D., R. Journal of Medicinal Chemistry, 59(10):4800-4811, 5, 2016. doi abstract bibtex 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 head group 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, including data from adipocyte and myoblast and cell differentiation assays.
@article{
title = {Identification of a Chemical Probe for Family VIII Bromodomains through Optimization of a Fragment Hit},
type = {article},
year = {2016},
pages = {4800-4811},
volume = {59},
month = {5},
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created = {2016-12-01T10:12:01.000Z},
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last_modified = {2018-07-09T12:39:49.663Z},
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citation_key = {Gerstenberger2016},
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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 head group 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, including data from adipocyte and myoblast and cell differentiation assays.},
bibtype = {article},
author = {Gerstenberger, Brian S. and Trzupek, John D. and Tallant, Cynthia and Fedorov, Oleg and Filippakopoulos, Panagis and Brennan, Paul E. and Fedele, Vita and Martin, Sarah and Picaud, Sarah and Rogers, Catherine and Parikh, Mihir and Taylor, Alexandria and Samas, Brian and O'Mahony, Alison and Berg, Ellen and Pallares, Gabriel and Torrey, Adam D. and Treiber, Daniel K. and Samardjiev, Ivan J. and Nasipak, Brian T. and Padilla-Benavides, Teresita and Wu, Qiong and Imbalzano, Anthony N. and Nickerson, Jeffrey A. and Bunnage, Mark E. and Müller, Susanne and Knapp, Stefan and Owen, Dafydd R.},
doi = {10.1021/acs.jmedchem.6b00012},
journal = {Journal of Medicinal Chemistry},
number = {10}
}