6fsy

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Crystal Structure of the first bromodomain of human BRD4 in complex with a 3,5-dimethylisoxazol ligand

Structural highlights

6fsy is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:E5Q, EDO
Gene:BRD4, HUNK1 (HUMAN)
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

Ligands for the bromodomain and extra-terminal domain (BET) family of bromodomains have shown promise as useful therapeutic agents for treating a range of cancers and inflammation. Here we report that our previously developed 3,5-dimethylisoxazole-based BET bromodomain ligand (OXFBD02) inhibits interactions of BRD4(1) with the RelA subunit of NF-kappaB, in addition to histone H4. This ligand shows a promising profile in a screen of the NCI-60 panel but was rapidly metabolised (t(1/2)=39.8min). Structure-guided optimisation of compound properties led to the development of the 3-pyridyl-derived OXFBD04. Molecular dynamics simulations assisted our understanding of the role played by an internal hydrogen bond in altering the affinity of this series of molecules for BRD4(1). OXFBD04 shows improved BRD4(1) affinity (IC50=166nM), optimised physicochemical properties (LE=0.43; LLE=5.74; SFI=5.96), and greater metabolic stability (t(1/2)=388min).

BET bromodomain ligands: Probing the WPF shelf to improve BRD4 bromodomain affinity and metabolic stability.,Jennings LE, Schiedel M, Hewings DS, Picaud S, Laurin CMC, Bruno PA, Bluck JP, Scorah AR, See L, Reynolds JK, Moroglu M, Mistry IN, Hicks A, Guzanov P, Clayton J, Evans CNG, Stazi G, Biggin PC, Mapp AK, Hammond EM, Humphreys PG, Filippakopoulos P, Conway SJ Bioorg Med Chem. 2018 Jul 15;26(11):2937-2957. doi: 10.1016/j.bmc.2018.05.003., Epub 2018 May 15. PMID:29776834[3]

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

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Citations
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BET bromodomain inhibitors: fragment-based in silico design using multi-target QSAR models.
Speck-Planche et al. (2019)
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6 other articles
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See Also

References

  1. ↑ 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
  2. ↑ 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
  3. ↑ Jennings LE, Schiedel M, Hewings DS, Picaud S, Laurin CMC, Bruno PA, Bluck JP, Scorah AR, See L, Reynolds JK, Moroglu M, Mistry IN, Hicks A, Guzanov P, Clayton J, Evans CNG, Stazi G, Biggin PC, Mapp AK, Hammond EM, Humphreys PG, Filippakopoulos P, Conway SJ. BET bromodomain ligands: Probing the WPF shelf to improve BRD4 bromodomain affinity and metabolic stability. Bioorg Med Chem. 2018 Jul 15;26(11):2937-2957. doi: 10.1016/j.bmc.2018.05.003., Epub 2018 May 15. PMID:29776834 doi:http://dx.doi.org/10.1016/j.bmc.2018.05.003

Contents


PDB ID 6fsy

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