7OE9

C-TERMINAL BROMODOMAIN OF HUMAN BRD2 WITH rac-N5-((1R,5S)-3-oxabicyclo[3.1.0]hexan-6-yl)-N7,3-dimethyl-3-phenyl-2,3-dihydrobenzofuran-5,7-dicarboxamide

Summary for 7OE9

• Entry DOI: 10.2210/pdb7oe9/pdb
• Related: 7OE8
• Descriptor: Bromodomain-containing protein 2, (3S)-N7,3-dimethyl-N5-[(1R,5S)-3-oxabicyclo[3.1.0]hexan-6-yl]-3-phenyl-2H-1-benzofuran-5,7-dicarboxamide, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: inhibitor, bromodomain, nuclear protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 13949.05

Authors

Chung, C. (deposition date: 2021-05-02, release date: 2021-07-28, Last modification date: 2024-05-01)

Primary citation

Lucas, S.C.C.,Atkinson, S.J.,Chung, C.W.,Davis, R.,Gordon, L.,Grandi, P.,Gray, J.J.R.,Grimes, T.,Phillipou, A.,Preston, A.G.,Prinjha, R.K.,Rioja, I.,Taylor, S.,Tomkinson, N.C.O.,Wall, I.,Watson, R.J.,Woolven, J.,Demont, E.H.
Optimization of a Series of 2,3-Dihydrobenzofurans as Highly Potent, Second Bromodomain (BD2)-Selective, Bromo and Extra-Terminal Domain (BET) Inhibitors.
J.Med.Chem., 64:10711-10741, 2021

PubMed Abstract: Herein, a series of 2,3-dihydrobenzofurans have been developed as highly potent bromo and extra-terminal domain (BET) inhibitors with 1000-fold selectivity for the second bromodomain (BD2) over the first bromodomain (BD1). Investment in the development of two orthogonal synthetic routes delivered inhibitors that were potent and selective but had raised clearance and suboptimal solubility. Insertion of a quaternary center into the 2,3-dihydrobenzofuran core blocked a key site of metabolism and improved the solubility. This led to the development of inhibitor (GSK852): a potent, 1000-fold-selective, highly soluble compound with good rat and dog pharmacokinetics.

PubMed: 34260229
DOI: 10.1021/acs.jmedchem.1c00344

Experimental method

X-RAY DIFFRACTION (1.602 Å)