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Title: Methylpyrrole inhibitors of BET bromodomains

Authors:
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Publication Date:
Sponsoring Org.:
USDOE
OSTI Identifier:
1414004
Grant/Contract Number:
AC02-06CH11357
Resource Type:
Journal Article: Publisher's Accepted Manuscript
Journal Name:
Bioorganic and Medicinal Chemistry Letters
Additional Journal Information:
Journal Volume: 27; Journal Issue: 10; Related Information: CHORUS Timestamp: 2017-12-18 20:24:19; Journal ID: ISSN 0960-894X
Publisher:
Elsevier
Country of Publication:
United Kingdom
Language:
English

Citation Formats

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., and McDaniel, Keith F.. Methylpyrrole inhibitors of BET bromodomains. United Kingdom: N. p., 2017. Web. doi:10.1016/j.bmcl.2017.02.057.
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.. Methylpyrrole inhibitors of BET bromodomains. United Kingdom. doi:10.1016/j.bmcl.2017.02.057.
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., and McDaniel, Keith F.. Mon . "Methylpyrrole inhibitors of BET bromodomains". United Kingdom. doi:10.1016/j.bmcl.2017.02.057.
@article{osti_1414004,
title = {Methylpyrrole inhibitors of BET bromodomains},
author = {Hasvold, Lisa A. and Sheppard, George S. and Wang, Le and Fidanze, Steven D. and Liu, Dachun and Pratt, John K. and Mantei, Robert A. and Wada, Carol K. and Hubbard, Robbert and Shen, Yu and Lin, Xiaoyu and Huang, Xiaoli and Warder, Scott E. and Wilcox, Denise and Li, Leiming and Buchanan, F. Greg and Smithee, Lauren and Albert, Daniel H. and Magoc, Terrance J. and Park, Chang H. and Petros, Andrew M. and Panchal, Sanjay C. and Sun, Chaohong and Kovar, Peter and Soni, Nirupama B. and Elmore, Steven W. and Kati, Warren M. and McDaniel, Keith F.},
abstractNote = {},
doi = {10.1016/j.bmcl.2017.02.057},
journal = {Bioorganic and Medicinal Chemistry Letters},
number = 10,
volume = 27,
place = {United Kingdom},
year = {Mon May 01 00:00:00 EDT 2017},
month = {Mon May 01 00:00:00 EDT 2017}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record at 10.1016/j.bmcl.2017.02.057

Citation Metrics:
Cited by: 2works
Citation information provided by
Web of Science

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  • 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.
  • Bromodomains are epigenetic readers that specifically bind to the acetyl lysine residues of histones and transcription factors. Small molecule BET bromodomain inhibitors can disrupt this interaction which leads to potential modulation of several disease states. Here we describe the binding properties of a novel BET inhibitor RVX-297 that is structurally related to the clinical compound RVX-208, currently undergoing phase III clinical trials for the treatment of cardiovascular diseases, but is distinctly different in its biological and pharmacokinetic profiles. We report that RVX-297 preferentially binds to the BD2 domains of the BET bromodomain and Extra Terminal (BET) family of protein. Wemore » demonstrate the differential binding modes of RVX-297 in BD1 and BD2 domains of BRD4 and BRD2 using X-ray crystallography, and describe the structural differences driving the BD2 selective binding of RVX-297. The isothermal titration calorimetry (ITC) data illustrate the related differential thermodynamics of binding of RVX-297 to single as well as dual BET bromodomains. - Highlights: • A novel inhibitor of BET bromodomains, RVX-297 is described. • The differential binding modes of RVX-297 in BD1 and BD2 domains of BRD4 and BRD2 using X-ray crystallography are described. • RVX-297 preferentially binds to the BD2 domains of the BET bromodomains. • The structural and thermodynamic properties of the BD2 selective binding of RVX-297 are characterized.« less