5F5Z

Crystal structure of the first bromodomain of human BRD4 in complex with MA2-014

Summary for 5F5Z

• Entry DOI: 10.2210/pdb5f5z/pdb
• Related: 5F60 5F61 5F62 5F63
• Descriptor: Bromodomain-containing protein 4, 2-methyl-~{N}-[3-[[5-methyl-2-[[4-(4-methylpiperazin-1-yl)phenyl]amino]pyrimidin-4-yl]amino]phenyl]propane-2-sulfonamide, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: bromodomain, cap, hunk1, mcap, protein binding-inhibitor complex, mitotic chromosome associated protein, cell cycle, inhibitor, transcription-inhibitor complex, transcription-transcription inhibitor complex, transcription/transcription inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus: O60885
• Total number of polymer chains: 1
• Total formula weight: 15733.18

Authors

Ember, S.W.,Zhu, J.-Y.,Schonbrunn, E. (deposition date: 2015-12-04, release date: 2017-04-05, Last modification date: 2023-09-27)

Primary citation

Ember, S.W.,Lambert, Q.T.,Berndt, N.,Gunawan, S.,Ayaz, M.,Tauro, M.,Zhu, J.Y.,Cranfill, P.J.,Greninger, P.,Lynch, C.C.,Benes, C.H.,Lawrence, H.R.,Reuther, G.W.,Lawrence, N.J.,Schonbrunn, E.
Potent Dual BET Bromodomain-Kinase Inhibitors as Value-Added Multitargeted Chemical Probes and Cancer Therapeutics.
Mol. Cancer Ther., 16:1054-1067, 2017

PubMed Abstract: Synergistic action of kinase and BET bromodomain inhibitors in cell killing has been reported for a variety of cancers. Using the chemical scaffold of the JAK2 inhibitor TG101348, we developed and characterized single agents which potently and simultaneously inhibit BRD4 and a specific set of oncogenic tyrosine kinases including JAK2, FLT3, RET, and ROS1. Lead compounds showed on-target inhibition in several blood cancer cell lines and were highly efficacious at inhibiting the growth of hematopoietic progenitor cells from patients with myeloproliferative neoplasm. Screening across 931 cancer cell lines revealed differential growth inhibitory potential with highest activity against bone and blood cancers and greatly enhanced activity over the single BET inhibitor JQ1. Gene drug sensitivity analyses and drug combination studies indicate synergism of BRD4 and kinase inhibition as a plausible reason for the superior potency in cell killing. Combined, our findings indicate promising potential of these agents as novel chemical probes and cancer therapeutics. .

PubMed: 28336808
DOI: 10.1158/1535-7163.MCT-16-0568-T

Experimental method

X-RAY DIFFRACTION (1.76 Å)