4w2r: Difference between revisions
New page: '''Unreleased structure''' The entry 4w2r is ON HOLD Authors: Gajiwala, K.S., Brooun, A., Liu, W., Deng, Y., Stewart, A.E. Description: Structure of Hs/AcPRC2 in complex with 5,8-dichl... |
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==Structure of Hs/AcPRC2 in complex with 5,8-dichloro-2-[(4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-7-[(R)-methoxy(oxetan-3-yl)methyl]-3,4-dihydroisoquinolin-1(2H)-one== | |||
<StructureSection load='4w2r' size='340' side='right'caption='[[4w2r]], [[Resolution|resolution]] 2.81Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4w2r]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Anolis_carolinensis Anolis carolinensis] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4W2R OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4W2R 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]] 2.81Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CJD:5,8-dichloro-2-[(4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-7-[(R)-methoxy(oxetan-3-yl)methyl]-3,4-dihydroisoquinolin-1(2H)-one'>CJD</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=4w2r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4w2r OCA], [https://pdbe.org/4w2r PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4w2r RCSB], [https://www.ebi.ac.uk/pdbsum/4w2r PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4w2r ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/G1KPH4_ANOCA G1KPH4_ANOCA] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
A new series of lactam-derived EZH2 inhibitors was designed via a ligand- and physicochemical property-based strategy to address metabolic stability and thermodynamic solubility issues associated with previous lead compound 1. The new inhibitors incorporated an sp3 hybridized carbon atom at the 7-position of the lactam moiety present in lead compound 1 as a replacement for a dimethylisoxazole group. This transformation enabled optimization of the physicochemical properties and potency compared to compound 1. Analysis of relationships between calculated logD (cLogD) values and in vitro metabolic stability and permeability parameters identified a clogD range that afforded an increased probability of achieving favorable ADME data in a single molecule. Compound 23a exhibited the best overlap of potency and pharmaceutical properties as well as robust tumor growth inhibition in vivo and was therefore advanced as a development candidate (PF-06821497). A crystal structure of 23a in complex with the three-protein PRC2 complex enabled understanding of the key structural features required for optimal binding. | |||
Optimization of orally bioavailable enhancer of zeste homolog 2 (EZH2) inhibitors using ligand and property-based design strategies: Identification of development candidate (R)-5,8-dichloro-7-(methoxy(oxetan-3-yl)methyl)-2-((4-methoxy-6-methyl-2-oxo-1,2- dihydropyridin-3-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one (PF-06821497).,Kung PP, Bingham P, Brooun A, Collins MR, Deng YL, Dinh DM, Fan C, Gajiwala KS, Grantner R, Gukasyan HJ, Hu W, Huang B, Kania RS, Kephart SE, Krivacic CT, Kumpf RA, Khamphavong P, Kraus M, Liu W, Maegley KA, Nguyen L, Ren S, Richter DT, Rollins RA, Sach NW, Sharma S, Sherrill J, Spangler JE, Stewart AE, Sutton SC, Uryu S, Verhelle D, Wang H, Wang S, Wythes M, Xin S, Yamazaki S, Zhu H, Zhu J, Zehnder L, Edwards MP J Med Chem. 2017 Dec 6. doi: 10.1021/acs.jmedchem.7b01375. PMID:29211475<ref>PMID:29211475</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 4w2r" style="background-color:#fffaf0;"></div> | ||
[[Category: Deng | |||
[[Category: | ==See Also== | ||
[[Category: Liu | *[[Polycomb complex proteins 3D structures|Polycomb complex proteins 3D structures]] | ||
[[Category: | == References == | ||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Anolis carolinensis]] | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Brooun A]] | |||
[[Category: Deng Y]] | |||
[[Category: Gajiwala KS]] | |||
[[Category: Liu W]] | |||
[[Category: Stewart AE]] | |||
Latest revision as of 10:27, 27 September 2023
Structure of Hs/AcPRC2 in complex with 5,8-dichloro-2-[(4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-7-[(R)-methoxy(oxetan-3-yl)methyl]-3,4-dihydroisoquinolin-1(2H)-oneStructure of Hs/AcPRC2 in complex with 5,8-dichloro-2-[(4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-7-[(R)-methoxy(oxetan-3-yl)methyl]-3,4-dihydroisoquinolin-1(2H)-one
Structural highlights
FunctionPublication Abstract from PubMedA new series of lactam-derived EZH2 inhibitors was designed via a ligand- and physicochemical property-based strategy to address metabolic stability and thermodynamic solubility issues associated with previous lead compound 1. The new inhibitors incorporated an sp3 hybridized carbon atom at the 7-position of the lactam moiety present in lead compound 1 as a replacement for a dimethylisoxazole group. This transformation enabled optimization of the physicochemical properties and potency compared to compound 1. Analysis of relationships between calculated logD (cLogD) values and in vitro metabolic stability and permeability parameters identified a clogD range that afforded an increased probability of achieving favorable ADME data in a single molecule. Compound 23a exhibited the best overlap of potency and pharmaceutical properties as well as robust tumor growth inhibition in vivo and was therefore advanced as a development candidate (PF-06821497). A crystal structure of 23a in complex with the three-protein PRC2 complex enabled understanding of the key structural features required for optimal binding. Optimization of orally bioavailable enhancer of zeste homolog 2 (EZH2) inhibitors using ligand and property-based design strategies: Identification of development candidate (R)-5,8-dichloro-7-(methoxy(oxetan-3-yl)methyl)-2-((4-methoxy-6-methyl-2-oxo-1,2- dihydropyridin-3-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one (PF-06821497).,Kung PP, Bingham P, Brooun A, Collins MR, Deng YL, Dinh DM, Fan C, Gajiwala KS, Grantner R, Gukasyan HJ, Hu W, Huang B, Kania RS, Kephart SE, Krivacic CT, Kumpf RA, Khamphavong P, Kraus M, Liu W, Maegley KA, Nguyen L, Ren S, Richter DT, Rollins RA, Sach NW, Sharma S, Sherrill J, Spangler JE, Stewart AE, Sutton SC, Uryu S, Verhelle D, Wang H, Wang S, Wythes M, Xin S, Yamazaki S, Zhu H, Zhu J, Zehnder L, Edwards MP J Med Chem. 2017 Dec 6. doi: 10.1021/acs.jmedchem.7b01375. PMID:29211475[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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