6cks

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Crystal Structure of BRD4 with QC4956

Structural highlights

6cks 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 1.72Å
Ligands:F5Y
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

The bromodomain and extra-terminal (BET) family of epigenetic proteins has attracted considerable attention in drug discovery given its involvement in regulating gene transcription. Screening a focused small molecule library based on the bromodomain pharmacophore resulted in the identification of 2-methylisoquinoline-1-one as a novel BET bromodomain-binding motif. Structure guided SAR exploration resulted in >10,000-fold potency improvement for the BRD4-BD1 bromodomain. Lead compounds exhibited excellent potencies in both biochemical and cellular assays in MYC-dependent cell lines. Compound 36 demonstrated good physicochemical properties and promising exposure levels in exploratory PK studies.

Design, synthesis and biological evaluation of novel 4-phenylisoquinolinone BET bromodomain inhibitors.,Bennett MJ, Wu Y, Boloor A, Matuszkiewicz J, O'Connell SM, Shi L, Stansfield RK, Del Rosario JR, Veal JM, Hosfield DJ, Xu J, Kaldor SW, Stafford JA, Betancort JM Bioorg Med Chem Lett. 2018 Apr 10. pii: S0960-894X(18)30325-1. doi:, 10.1016/j.bmcl.2018.04.016. PMID:29657099[3]

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

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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. ↑ Bennett MJ, Wu Y, Boloor A, Matuszkiewicz J, O'Connell SM, Shi L, Stansfield RK, Del Rosario JR, Veal JM, Hosfield DJ, Xu J, Kaldor SW, Stafford JA, Betancort JM. Design, synthesis and biological evaluation of novel 4-phenylisoquinolinone BET bromodomain inhibitors. Bioorg Med Chem Lett. 2018 Apr 10. pii: S0960-894X(18)30325-1. doi:, 10.1016/j.bmcl.2018.04.016. PMID:29657099 doi:http://dx.doi.org/10.1016/j.bmcl.2018.04.016

Contents


PDB ID 6cks

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OCA

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