7zjp

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==Optimization of TEAD P-Site Binding Fragment Hit into In Vivo Active Lead MSC-4106==
==Optimization of TEAD P-Site Binding Fragment Hit into In Vivo Active Lead MSC-4106==
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<StructureSection load='7zjp' size='340' side='right'caption='[[7zjp]]' scene=''>
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<StructureSection load='7zjp' size='340' side='right'caption='[[7zjp]], [[Resolution|resolution]] 2.19&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7ZJP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7ZJP FirstGlance]. <br>
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<table><tr><td colspan='2'>[[7zjp]] is a 2 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=7ZJP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7ZJP FirstGlance]. <br>
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</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=7zjp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7zjp OCA], [https://pdbe.org/7zjp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7zjp RCSB], [https://www.ebi.ac.uk/pdbsum/7zjp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7zjp ProSAT]</span></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.19&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=JJU:2-methyl-4-[4-(trifluoromethyl)phenyl]pyrazolo[3,4-b]indole-7-carboxylic+acid'>JJU</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7zjp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7zjp OCA], [https://pdbe.org/7zjp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7zjp RCSB], [https://www.ebi.ac.uk/pdbsum/7zjp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7zjp ProSAT]</span></td></tr>
</table>
</table>
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== Disease ==
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[https://www.uniprot.org/uniprot/TEAD1_HUMAN TEAD1_HUMAN] Defects in TEAD1 are the cause of Sveinsson chorioretinal atrophy (SCRA) [MIM:[https://omim.org/entry/108985 108985]; also known as atrophia areata (AA) or helicoidal peripapillary chorioretinal degeneration (HPCD). SCRA is characterized by symmetrical lesions radiating from the optic disk involving the retina and the choroid.<ref>PMID:18579750</ref> <ref>PMID:20123905</ref> <ref>PMID:15016762</ref>
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== Function ==
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[https://www.uniprot.org/uniprot/TEAD1_HUMAN TEAD1_HUMAN] Transcription factor which plays a key role in the Hippo signaling pathway, a pathway involved in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. The core of this pathway is composed of a kinase cascade wherein MST1/MST2, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ. Acts by mediating gene expression of YAP1 and WWTR1/TAZ, thereby regulating cell proliferation, migration and epithelial mesenchymal transition (EMT) induction. Binds specifically and cooperatively to the SPH and GT-IIC 'enhansons' (5'-GTGGAATGT-3') and activates transcription in vivo in a cell-specific manner. The activation function appears to be mediated by a limiting cell-specific transcriptional intermediary factor (TIF). Involved in cardiac development. Binds to the M-CAT motif.<ref>PMID:18579750</ref> <ref>PMID:19324877</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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The dysregulated Hippo pathway and, consequently, hyperactivity of the transcriptional YAP/TAZ-TEAD complexes is associated with diseases such as cancer. Prevention of YAP/TAZ-TEAD triggered gene transcription is an attractive strategy for therapeutic intervention. The deeply buried and conserved lipidation pocket (P-site) of the TEAD transcription factors is druggable. The discovery and optimization of a P-site binding fragment (1) are described. Utilizing structure-based design, enhancement in target potency was engineered into the hit, capitalizing on the established X-ray structure of TEAD1. The efforts culminated in the optimized in vivo tool MSC-4106, which exhibited desirable potency, mouse pharmacokinetic properties, and in vivo efficacy. In close correlation to compound exposure, the time- and dose-dependent downregulation of a proximal biomarker could be shown.
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Optimization of TEAD P-Site Binding Fragment Hit into In Vivo Active Lead MSC-4106.,Heinrich T, Peterson C, Schneider R, Garg S, Schwarz D, Gunera J, Seshire A, Kotzner L, Schlesiger S, Musil D, Schilke H, Doerfel B, Diehl P, Bopple P, Lemos AR, Sousa PMF, Freire F, Bandeiras TM, Carswell E, Pearson N, Sirohi S, Hooker M, Trivier E, Broome R, Balsiger A, Crowden A, Dillon C, Wienke D J Med Chem. 2022 Jun 28. doi: 10.1021/acs.jmedchem.2c00403. PMID:35763499<ref>PMID:35763499</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 7zjp" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Balsiger A]]
[[Category: Balsiger A]]

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Optimization of TEAD P-Site Binding Fragment Hit into In Vivo Active Lead MSC-4106

PDB ID 7zjp

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