6HDQ

N-TERMINAL BROMODOMAIN OF HUMAN BRD4 WITH : 8-(((1R,2R,3R,5S)-2-(2-(4,4-difluorocyclohexyl)ethyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)-3-methyl-5-(5-methylpyridin-3-yl)-1,7-naphthyridin-2(1H)-one

Summary for 6HDQ

• Entry DOI: 10.2210/pdb6hdq/pdb
• Descriptor: Bromodomain-containing protein 4, 1,2-ETHANEDIOL, 8-(((1R,2R,3R,5S)-2-(2-(4,4-difluorocyclohexyl)ethyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)-3-methyl-5-(5-methylpyridin-3-yl)-1,7-naphthyridin-2(1H)-one, ... (4 entities in total)
• Functional Keywords: inhibitor, histone, epigenetic reader, bromodomain, brd4, bromodomain containing protein 4, antagonist, transcription
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 15683.09

Authors

Chung, C. (deposition date: 2018-08-18, release date: 2018-09-26, Last modification date: 2024-05-15)

Primary citation

Bamborough, P.,Chung, C.W.,Furze, R.C.,Grandi, P.,Michon, A.M.,Watson, R.J.,Mitchell, D.J.,Barnett, H.,Prinjha, R.K.,Rau, C.,Sheppard, R.J.,Werner, T.,Demont, E.H.
Aiming to Miss a Moving Target: Bromo and Extra Terminal Domain (BET) Selectivity in Constrained ATAD2 Inhibitors.
J. Med. Chem., 61:8321-8336, 2018

PubMed Abstract: ATAD2 is a cancer-associated protein whose bromodomain has been described as among the least druggable of its class. In our recent disclosure of the first chemical probe against this bromodomain, GSK8814 (6), we described the use of a conformationally constrained methoxy piperidine to gain selectivity over the BET bromodomains. Here we describe an orthogonal conformational restriction strategy of the piperidine ring to give potent and selective tropane inhibitors and show structural insights into why this was more challenging than expected. Greater understanding of why different rational approaches succeeded or failed should help in the future design of selectivity in the bromodomain family.

PubMed: 30226378
DOI: 10.1021/acs.jmedchem.8b00862

Experimental method

X-RAY DIFFRACTION (1.7 Å)