7uzn
From Proteopedia
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==CRYSTAL STRUCTURE OF THE FIRST BROMODOMAIN OF HUMAN BRD4 IN COMPLEX WITH BMT-206059 AKA 2-{(3M)-3-(1,4-DIMETHYL-1H-1,2,3-TRIAZOL-5-YL)-8-FLUORO-5-[(S)-(OXAN-4-YL)(PHENYL)METHYL]-5H-PYRIDO[3,2-b]INDOL-7-YL}PROPAN-2-OL, TRIPLY DEUTERATED ON THE 4-METHYL GROUP== | ==CRYSTAL STRUCTURE OF THE FIRST BROMODOMAIN OF HUMAN BRD4 IN COMPLEX WITH BMT-206059 AKA 2-{(3M)-3-(1,4-DIMETHYL-1H-1,2,3-TRIAZOL-5-YL)-8-FLUORO-5-[(S)-(OXAN-4-YL)(PHENYL)METHYL]-5H-PYRIDO[3,2-b]INDOL-7-YL}PROPAN-2-OL, TRIPLY DEUTERATED ON THE 4-METHYL GROUP== | ||
| - | <StructureSection load='7uzn' size='340' side='right'caption='[[7uzn]]' scene=''> | + | <StructureSection load='7uzn' size='340' side='right'caption='[[7uzn]], [[Resolution|resolution]] 1.69Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7UZN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7UZN FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7uzn]] 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=7UZN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7UZN FirstGlance]. <br> |
| - | </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=7uzn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7uzn OCA], [https://pdbe.org/7uzn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7uzn RCSB], [https://www.ebi.ac.uk/pdbsum/7uzn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7uzn ProSAT]</span></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]] 1.685Å</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=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=PQF:2-{(3M)-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-8-fluoro-5-[(S)-(oxan-4-yl)(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol'>PQF</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=7uzn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7uzn OCA], [https://pdbe.org/7uzn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7uzn RCSB], [https://www.ebi.ac.uk/pdbsum/7uzn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7uzn ProSAT]</span></td></tr> | ||
</table> | </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 == | ||
| + | We describe the synthesis of triazole-containing carboline derivatives and their utility as bromodomain and extra-terminal (BET) inhibitors. A convergent synthetic route permitted the detailed investigation of deuteration and fluorination strategies to reduce clearance while maintaining a favorable in vitro profile. This work led to the identification of a potent BET inhibitor, 2-{8-fluoro-3-[4-((2)H3)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-(oxan-4-yl) (phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol (15), which demonstrated reduced clearance and an improved pharmacokinetic (PK) profile across preclinical species. Importantly, no major metabolite was observed when 15 was incubated with human hepatocytes (hHEP) for 2 h. This study culminated with the evaluation of 15 in a mouse triple-negative breast cancer (TNBC) tumor model where it demonstrated robust efficacy at low doses. | ||
| + | |||
| + | Development of BET Inhibitors as Potential Treatments for Cancer: Optimization of Pharmacokinetic Properties.,Hill MD, Fang H, Norris D, Delucca GV, Huang H, DeBenedetto M, Quesnelle C, Schmitz WD, Tokarski JS, Sheriff S, Yan C, Fanslau C, Haarhoff Z, Huang C, Kramer M, Madari S, Menard K, Monereau L, Morrison J, Raghavan N, Shields EE, Simmermacher-Mayer J, Sinz M, Tye CK, Westhouse R, Xie C, Zhang H, Zhang L, Zvyaga T, Lee F, Gavai AV, Degnan AP ACS Med Chem Lett. 2022 Jul 5;13(7):1165-1171. doi:, 10.1021/acsmedchemlett.2c00219. eCollection 2022 Jul 14. PMID:35859878<ref>PMID:35859878</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 7uzn" style="background-color:#fffaf0;"></div> | ||
| + | |||
| + | ==See Also== | ||
| + | *[[Bromodomain-containing protein 3D structures|Bromodomain-containing protein 3D structures]] | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Sheriff S]] | [[Category: Sheriff S]] | ||
Current revision
CRYSTAL STRUCTURE OF THE FIRST BROMODOMAIN OF HUMAN BRD4 IN COMPLEX WITH BMT-206059 AKA 2-{(3M)-3-(1,4-DIMETHYL-1H-1,2,3-TRIAZOL-5-YL)-8-FLUORO-5-[(S)-(OXAN-4-YL)(PHENYL)METHYL]-5H-PYRIDO[3,2-b]INDOL-7-YL}PROPAN-2-OL, TRIPLY DEUTERATED ON THE 4-METHYL GROUP
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