7t3f: Difference between revisions

Latest revision as of 16:58, 18 October 2023

Development of BRD4 inhibitors as arsenicals antidotes

Structural highlights

7t3f 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 1.28Å
Ligands:	EM0, GOL
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

Arsenicals belong to the class of chemical warfare agents known as vesicants, which are highly reactive, toxic and cause robust inflammatory response. Cutaneous exposure to arsenicals causes a wide range of systemic organ damage, beginning with cutaneous injuries, and later manifest multi-organ damage and death. Thus, the development of suitable antidotes that can effectively block injury following exposure to these agents is of great importance. Bromodomain 4 (BRD4), a member of the bromodomain and extra terminal domain (BET) family, plays crucial role in regulating transcription of inflammatory, proliferation and cell cycle genes. In this context, the development of potent small molecule inhibitors of BRD4 could serve as potential antidotes for arsenicals. Herein, we describe the synthesis and biological evaluation of a series of compounds.

Development of BRD4 inhibitors as anti-inflammatory agents and antidotes for arsenicals.,Yatchang MF, Mathew B, Srivastava RK, Khan J, Muzaffar S, Zhang S, Wu M, Zhai L, Ruiz P, Agarwal A, Bostwick JR, Suto MJ, Athar M, Augelli-Szafran CE Bioorg Med Chem Lett. 2022 May 15;64:128696. doi: 10.1016/j.bmcl.2022.128696., Epub 2022 Mar 19. PMID:35318165^[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
↑ Yatchang MF, Mathew B, Srivastava RK, Khan J, Muzaffar S, Zhang S, Wu M, Zhai L, Ruiz P, Agarwal A, Bostwick JR, Suto MJ, Athar M, Augelli-Szafran CE. Development of BRD4 inhibitors as anti-inflammatory agents and antidotes for arsenicals. Bioorg Med Chem Lett. 2022 May 15;64:128696. doi: 10.1016/j.bmcl.2022.128696., Epub 2022 Mar 19. PMID:35318165 doi:https://dx.doi.org/10.1016/j.bmcl.2022.128696

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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] Yatchang MF, Mathew B, Srivastava RK, Khan J, Muzaffar S, Zhang S, Wu M, Zhai L, Ruiz P, Agarwal A, Bostwick JR, Suto MJ, Athar M, Augelli-Szafran CE. Development of BRD4 inhibitors as anti-inflammatory agents and antidotes for arsenicals. Bioorg Med Chem Lett. 2022 May 15;64:128696. doi: 10.1016/j.bmcl.2022.128696., Epub 2022 Mar 19. PMID:35318165 doi:https://dx.doi.org/10.1016/j.bmcl.2022.128696

[1]

[2]

[3]

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[7t3f]] 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=7T3F OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7T3F FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EM0:4-fluoro-3-methyl-N-(3-methyl-2-oxo-1,2,3,4-tetrahydroquinazolin-6-yl)benzene-1-sulfonamide'>EM0</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.28&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EM0:4-fluoro-3-methyl-N-(3-methyl-2-oxo-1,2,3,4-tetrahydroquinazolin-6-yl)benzene-1-sulfonamide'>EM0</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</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=7t3f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7t3f OCA], [https://pdbe.org/7t3f PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7t3f RCSB], [https://www.ebi.ac.uk/pdbsum/7t3f PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7t3f 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>
+[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).
+[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 ==
@@ Line 20: / Line 21: @@
 </div>
 <div class="pdbe-citations 7t3f" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Bromodomain-containing protein 3D structures|Bromodomain-containing protein 3D structures]]
 == References ==
 <references/>

7t3f: Difference between revisions

Latest revision as of 16:58, 18 October 2023

Development of BRD4 inhibitors as arsenicals antidotes

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

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