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Potent and Selective N-Terminal BRD4 Bromodomain Inhibitors by Targeting Non-Conserved Residues and Structured Water Displacement
preprintsubmitted on 20.04.2020, 16:34 and posted on 23.04.2020, 05:28 by Huarui Cui, Anand Divakaran, Anil K. Pandey, Jorden A. Johnson, huda zahid, zachary hoell, mikael ellingson, ke shi, Hideki Aihara, Daniel A. Harki, william pomerantz
This manuscript focuses on the structure-based design of selective inhibitors of the first bromodomain of BRD4. This manuscript uses describes organic synthesis to make inhibitors, and biophysical analysis to evaluate their inhibitor potency in competive inhibition assays (fluorescence anisotropy assays and AlphaScreen). Binding mode is evaluate from protein co-crystal structures. Cell activity is evaluated in cell viability assays, target engagement CETSA assays analyzed via western blot, and inhibition of Myc via western blot analysis.