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5mli

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N-TERMINAL BROMODOMAIN OF HUMAN BRD4 WITH 4-chloro-2-methyl-5-(methylamino)pyridazin-3(2H)-one

Structural highlights

5mli is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.63Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

BRD4_HUMAN Note=A chromosomal aberration involving BRD4 is found in a rare, aggressive, and lethal carcinoma arising in midline organs of young people. Translocation t(15;19)(q14;p13) with NUT which produces a BRD4-NUT fusion protein.^[1] ^[2]

Function

BRD4_HUMAN Plays a role in a process governing chromosomal dynamics during mitosis (By similarity).

Publication Abstract from PubMed

p300/CREB binding protein associated factor (PCAF/KAT2B) and general control nonderepressible 5 (GCN5/KAT2A) are multidomain proteins that have been implicated in retroviral infection, inflammation pathways, and cancer development. However, outside of viral replication, little is known about the dependence of these effects on the C-terminal bromodomain. Herein, we report GSK4027 as a chemical probe for the PCAF/GCN5 bromodomain, together with GSK4028 as an enantiomeric negative control. The probe was optimized from a weakly potent, nonselective pyridazinone hit to deliver high potency for the PCAF/GCN5 bromodomain, high solubility, cellular target engagement, and >/=18000-fold selectivity over the BET family, together with >/=70-fold selectivity over the wider bromodomain families.

Discovery of a Potent, Cell Penetrant, and Selective p300/CBP-Associated Factor (PCAF)/General Control Nonderepressible 5 (GCN5) Bromodomain Chemical Probe.,Humphreys PG, Bamborough P, Chung CW, Craggs PD, Gordon L, Grandi P, Hayhow TG, Hussain J, Jones KL, Lindon M, Michon AM, Renaux JF, Suckling CJ, Tough DF, Prinjha RK J Med Chem. 2017 Jan 26;60(2):695-709. doi: 10.1021/acs.jmedchem.6b01566. Epub, 2017 Jan 9. PMID:28002667^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ French CA, Miyoshi I, Kubonishi I, Grier HE, Perez-Atayde AR, Fletcher JA. BRD4-NUT fusion oncogene: a novel mechanism in aggressive carcinoma. Cancer Res. 2003 Jan 15;63(2):304-7. PMID:12543779
↑ French CA, Miyoshi I, Aster JC, Kubonishi I, Kroll TG, Dal Cin P, Vargas SO, Perez-Atayde AR, Fletcher JA. BRD4 bromodomain gene rearrangement in aggressive carcinoma with translocation t(15;19). Am J Pathol. 2001 Dec;159(6):1987-92. PMID:11733348 doi:10.1016/S0002-9440(10)63049-0
↑ Humphreys PG, Bamborough P, Chung CW, Craggs PD, Gordon L, Grandi P, Hayhow TG, Hussain J, Jones KL, Lindon M, Michon AM, Renaux JF, Suckling CJ, Tough DF, Prinjha RK. Discovery of a Potent, Cell Penetrant, and Selective p300/CBP-Associated Factor (PCAF)/General Control Nonderepressible 5 (GCN5) Bromodomain Chemical Probe. J Med Chem. 2017 Jan 26;60(2):695-709. doi: 10.1021/acs.jmedchem.6b01566. Epub, 2017 Jan 9. PMID:28002667 doi:http://dx.doi.org/10.1021/acs.jmedchem.6b01566