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Potent and Selective N-Terminal BRD4 Bromodomain Inhibitors by Targeting Non-Conserved Residues and Structured Water Displacement

preprint
submitted 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.

Funding

Masonic cancer center

R35-GM118047

R01-GM110129

15SDG25710427

T32-GM008347-23

T32-GM008700

P30-GM124165

S10-RR029205

History

Email Address of Submitting Author

wcp@umn.edu

Institution

University of Minnesota

Country

USA

ORCID For Submitting Author

0000-0002-0163-4078

Declaration of Conflict of Interest

No conflict of interest

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