4c67: Difference between revisions

Latest revision as of 11:09, 9 May 2024

Discovery of Epigenetic Regulator I-BET762: Lead Optimization to Afford a Clinical Candidate Inhibitor of the BET Bromodomains

Structural highlights

4c67 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 1.55Å
Ligands:	EDO, L5S
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 bromo and extra C-terminal domain (BET) family of bromodomains are involved in binding epigenetic marks on histone proteins, more specifically acetylated lysine residues. This paper describes the discovery and structure-activity relationship (SAR) of potent benzodiazepine inhibitors that disrupt the function of the BET family of bromodomains (BRD2, BRD3 and BRD4). This work has yielded a potent, selective compound I-BET762 that is now under evaluation in a phase I/II clinical trial for nuclear protein in testis (NUT) midline carcinoma and other cancers.

Discovery of epigenetic regulator I-BET762: lead optimization to afford a clinical candidate inhibitor of the BET bromodomains.,Mirguet O, Gosmini R, Toum J, Clement CA, Barnathan M, Brusq JM, Mordaunt JE, Grimes R, Crowe M, Pineau O, Ajakane M, Daugan A, Jeffrey P, Cutler L, Haynes A, Smithers N, Chung CW, Bamborough P, Uings IJ, Lewis T, Witherington J, Parr N, Prinjha R, Nicodeme E J Med Chem. 2013 Sep 9. PMID:24015967^[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
↑ Mirguet O, Gosmini R, Toum J, Clement CA, Barnathan M, Brusq JM, Mordaunt JE, Grimes R, Crowe M, Pineau O, Ajakane M, Daugan A, Jeffrey P, Cutler L, Haynes A, Smithers N, Chung CW, Bamborough P, Uings IJ, Lewis T, Witherington J, Parr N, Prinjha R, Nicodeme E. Discovery of epigenetic regulator I-BET762: lead optimization to afford a clinical candidate inhibitor of the BET bromodomains. J Med Chem. 2013 Sep 9. PMID:24015967 doi:10.1021/jm401088k

Proteopedia Page Contributors and Editors (what is this?)

OCA

[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] Mirguet O, Gosmini R, Toum J, Clement CA, Barnathan M, Brusq JM, Mordaunt JE, Grimes R, Crowe M, Pineau O, Ajakane M, Daugan A, Jeffrey P, Cutler L, Haynes A, Smithers N, Chung CW, Bamborough P, Uings IJ, Lewis T, Witherington J, Parr N, Prinjha R, Nicodeme E. Discovery of epigenetic regulator I-BET762: lead optimization to afford a clinical candidate inhibitor of the BET bromodomains. J Med Chem. 2013 Sep 9. PMID:24015967 doi:10.1021/jm401088k

[1]

[2]

[3]

@@ Line 1: / Line 1: @@
-{{STRUCTURE_4c67|  PDB=4c67  |  SCENE=  }}
-===Discovery of Epigenetic Regulator I-BET762: Lead Optimization to Afford a Clinical Candidate Inhibitor of the BET Bromodomains===
-{{ABSTRACT_PUBMED_24015967}}
-==Disease==
+==Discovery of Epigenetic Regulator I-BET762: Lead Optimization to Afford a Clinical Candidate Inhibitor of the BET Bromodomains==
-[[http://www.uniprot.org/uniprot/BRD4_HUMAN 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.<ref>PMID:12543779</ref> <ref>PMID:11733348</ref>
+<StructureSection load='4c67' size='340' side='right'caption='[[4c67]], [[Resolution|resolution]] 1.55&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[4c67]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4C67 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4C67 FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.55&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=L5S:13-METHYL-7-PHENYL-3-THIA-1,8,11,12-TETRAAZATRICYCLO+TRIDECA-2(6),4,7,10,12-PENTAENE'>L5S</scene></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4c67 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4c67 OCA], [https://pdbe.org/4c67 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4c67 RCSB], [https://www.ebi.ac.uk/pdbsum/4c67 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4c67 ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[https://www.uniprot.org/uniprot/BRD4_HUMAN 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.<ref>PMID:12543779</ref> <ref>PMID:11733348</ref>
+== Function ==
+[https://www.uniprot.org/uniprot/BRD4_HUMAN BRD4_HUMAN] Plays a role in a process governing chromosomal dynamics during mitosis (By similarity).
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+The bromo and extra C-terminal domain (BET) family of bromodomains are involved in binding epigenetic marks on histone proteins, more specifically acetylated lysine residues. This paper describes the discovery and structure-activity relationship (SAR) of potent benzodiazepine inhibitors that disrupt the function of the BET family of bromodomains (BRD2, BRD3 and BRD4). This work has yielded a potent, selective compound I-BET762 that is now under evaluation in a phase I/II clinical trial for nuclear protein in testis (NUT) midline carcinoma and other cancers.
-==Function==
+Discovery of epigenetic regulator I-BET762: lead optimization to afford a clinical candidate inhibitor of the BET bromodomains.,Mirguet O, Gosmini R, Toum J, Clement CA, Barnathan M, Brusq JM, Mordaunt JE, Grimes R, Crowe M, Pineau O, Ajakane M, Daugan A, Jeffrey P, Cutler L, Haynes A, Smithers N, Chung CW, Bamborough P, Uings IJ, Lewis T, Witherington J, Parr N, Prinjha R, Nicodeme E J Med Chem. 2013 Sep 9. PMID:24015967<ref>PMID:24015967</ref>
-[[http://www.uniprot.org/uniprot/BRD4_HUMAN BRD4_HUMAN]] Plays a role in a process governing chromosomal dynamics during mitosis (By similarity).
-==About this Structure==
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[4c67]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4C67 OCA].
+</div>
+<div class="pdbe-citations 4c67" style="background-color:#fffaf0;"></div>
-==Reference==
+==See Also==
-<ref group="xtra">PMID:024015967</ref><references group="xtra"/><references/>
+*[[Bromodomain-containing protein 3D structures|Bromodomain-containing protein 3D structures]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
 [[Category: Homo sapiens]]
-[[Category: Chung, C.]]
+[[Category: Large Structures]]
-[[Category: Mirguet, O.]]
+[[Category: Chung C]]
-[[Category: Antagonist]]
+[[Category: Mirguet O]]
-[[Category: Bromodomain containing protein 4]]
-[[Category: Cell cycle]]
-[[Category: Epigenetic reader brd4]]
-[[Category: Histone]]

4c67: Difference between revisions

Latest revision as of 11:09, 9 May 2024

Discovery of Epigenetic Regulator I-BET762: Lead Optimization to Afford a Clinical Candidate Inhibitor of the BET Bromodomains

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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