5UEW

BRD2 Bromodomain2 with A-1360579

Summary for 5UEW

• Entry DOI: 10.2210/pdb5uew/pdb
• Related: 5UEO 5UEP 5UEQ 5UER 5UES 5UET 5UEU 5UEV 5UEX 5UEY 5UEZ 5UF0
• Descriptor: Bromodomain-containing protein 2, N-[3-(4-methoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-phenoxyphenyl]methanesulfonamide (3 entities in total)
• Functional Keywords: signaling protein-inhibitor complex, signaling protein/inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus : P25440
• Total number of polymer chains: 2
• Total formula weight: 26850.77

Authors

Park, C.H. (deposition date: 2017-01-03, release date: 2017-05-10, Last modification date: 2024-03-06)

Primary citation

Wang, L.,Pratt, J.K.,Soltwedel, T.,Sheppard, G.S.,Fidanze, S.D.,Liu, D.,Hasvold, L.A.,Mantei, R.A.,Holms, J.H.,McClellan, W.J.,Wendt, M.D.,Wada, C.,Frey, R.,Hansen, T.M.,Hubbard, R.,Park, C.H.,Li, L.,Magoc, T.J.,Albert, D.H.,Lin, X.,Warder, S.E.,Kovar, P.,Huang, X.,Wilcox, D.,Wang, R.,Rajaraman, G.,Petros, A.M.,Hutchins, C.W.,Panchal, S.C.,Sun, C.,Elmore, S.W.,Shen, Y.,Kati, W.M.,McDaniel, K.F.
Fragment-Based, Structure-Enabled Discovery of Novel Pyridones and Pyridone Macrocycles as Potent Bromodomain and Extra-Terminal Domain (BET) Family Bromodomain Inhibitors.
J. Med. Chem., 60:3828-3850, 2017

PubMed Abstract: Members of the BET family of bromodomain containing proteins have been identified as potential targets for blocking proliferation in a variety of cancer cell lines. A two-dimensional NMR fragment screen for binders to the bromodomains of BRD4 identified a phenylpyridazinone fragment with a weak binding affinity (1, K = 160 μM). SAR investigation of fragment 1, aided by X-ray structure-based design, enabled the synthesis of potent pyridone and macrocyclic pyridone inhibitors exhibiting single digit nanomolar potency in both biochemical and cell based assays. Advanced analogs in these series exhibited high oral exposures in rodent PK studies and demonstrated significant tumor growth inhibition efficacy in mouse flank xenograft models.

PubMed: 28368119
DOI: 10.1021/acs.jmedchem.7b00017

Experimental method

X-RAY DIFFRACTION (1.83 Å)