5kdh

From Proteopedia

CRYSTAL STRUCTURE OF THE FIRST BROMODOMAIN OF HUMAN BRD4 IN COMPLEX WITH A DIHYDROPYRIDOPYRIMIDINE SCAFFOLD INHIBITOR

Structural highlights

5kdh 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 1.5Å
Ligands:	6RX, EDO, SO4
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

Chemical inhibition of epigenetic regulatory proteins BrdT and Brd4 is emerging as a promising therapeutic strategy in contraception, cancer, and heart disease. We report an easily synthesized dihydropyridopyrimidine pan-BET inhibitor scaffold, which was uncovered via a virtual screen followed by testing in a fluorescence anisotropy assay. Dihydropyridopyimidine 3 was subjected to further characterization and is highly selective for the BET family of bromodomains. Structure-activity relationship data and ligand deconstruction highlight the importance of the substitution of the uracil moiety for potency and selectivity. Compound 3 was also cocrystallized with Brd4 for determining the ligand binding pose and rationalizing subsequent structure-activity data. An additional series of dihydropyridopyrimidines was synthesized to exploit the proximity of a channel near the ZA loop of Brd4, leading to compounds with submicromolar affinity and cellular target engagement. Given these findings, novel and easily synthesized inhibitors are being introduced to the growing field of bromodomain inhibitor development.

BET Bromodomain Inhibitors with One-Step Synthesis Discovered from Virtual Screen.,Ayoub AM, Hawk LML, Herzig RJ, Jiang J, Wisniewski AJ, Gee CT, Zhao P, Zhu JY, Berndt N, Offei-Addo NK, Scott TG, Qi J, Bradner JE, Ward TR, Schonbrunn E, Georg GI, Pomerantz WCK J Med Chem. 2017 Jun 22;60(12):4805-4817. doi: 10.1021/acs.jmedchem.6b01336. Epub, 2017 Jun 7. PMID:28535045^[3]

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

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Citations

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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
↑ Ayoub AM, Hawk LML, Herzig RJ, Jiang J, Wisniewski AJ, Gee CT, Zhao P, Zhu JY, Berndt N, Offei-Addo NK, Scott TG, Qi J, Bradner JE, Ward TR, Schonbrunn E, Georg GI, Pomerantz WCK. BET Bromodomain Inhibitors with One-Step Synthesis Discovered from Virtual Screen. J Med Chem. 2017 Jun 22;60(12):4805-4817. doi: 10.1021/acs.jmedchem.6b01336. Epub, 2017 Jun 7. PMID:28535045 doi:http://dx.doi.org/10.1021/acs.jmedchem.6b01336

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

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PDB ID 5kdh

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Categories: Homo sapiens | Large Structures | Schonbrunn E | Zhu J-Y

5kdh

From Proteopedia

CRYSTAL STRUCTURE OF THE FIRST BROMODOMAIN OF HUMAN BRD4 IN COMPLEX WITH A DIHYDROPYRIDOPYRIMIDINE SCAFFOLD INHIBITOR

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

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