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==Discovery of a KRAS G12C Inhibitor in vivo Tool Compound starting from an HSQC-NMR based Fragment Hit== | |||
<StructureSection load='7u8h' size='340' side='right'caption='[[7u8h]], [[Resolution|resolution]] 1.70Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[7u8h]] is a 4 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=7U8H OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7U8H 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]] 1.702Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2XO:1H-BENZIMIDAZOL-2-YLMETHANETHIOL'>2XO</scene>, <scene name='pdbligand=GDP:GUANOSINE-5-DIPHOSPHATE'>GDP</scene>, <scene name='pdbligand=LX6:2-amino-4,5,6,7-tetrahydro-1-benzothiophene-3-carbonitrile'>LX6</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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=7u8h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7u8h OCA], [https://pdbe.org/7u8h PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7u8h RCSB], [https://www.ebi.ac.uk/pdbsum/7u8h PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7u8h ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/A0A6D2XGP1_PONAB A0A6D2XGP1_PONAB] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Activating mutations in KRAS are the most frequent oncogenic alterations in cancer. The oncogenic hotspot position 12, located at the lip of the switch II pocket, offers a covalent attachment point for KRAS(G12C) inhibitors. To date, KRAS(G12C) inhibitors have been discovered by first covalently binding to the cysteine at position 12 and then optimizing pocket binding. We report on the discovery of the in vivo active KRAS(G12C) inhibitor BI-0474 using a different approach, in which small molecules that bind reversibly to the switch II pocket were identified and then optimized for non-covalent binding using structure-based design. Finally, the Michael acceptor containing warhead was attached. Our approach offers not only an alternative approach to discovering KRAS(G12C) inhibitors but also provides a starting point for the discovery of inhibitors against other oncogenic KRAS mutants. | |||
Fragment Optimization of Reversible Binding to the Switch II Pocket on KRAS Leads to a Potent, In Vivo Active KRAS(G12C) Inhibitor.,Broker J, Waterson AG, Smethurst C, Kessler D, Bottcher J, Mayer M, Gmaschitz G, Phan J, Little A, Abbott JR, Sun Q, Gmachl M, Rudolph D, Arnhof H, Rumpel K, Savarese F, Gerstberger T, Mischerikow N, Treu M, Herdeis L, Wunberg T, Gollner A, Weinstabl H, Mantoulidis A, Kramer O, McConnell DB, W Fesik S J Med Chem. 2022 Oct 27. doi: 10.1021/acs.jmedchem.2c01120. PMID:36300829<ref>PMID:36300829</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 7u8h" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[GTPase KRas 3D structures|GTPase KRas 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Fesik SW]] | |||
[[Category: Phan J]] | |||
Latest revision as of 12:50, 25 October 2023
Discovery of a KRAS G12C Inhibitor in vivo Tool Compound starting from an HSQC-NMR based Fragment HitDiscovery of a KRAS G12C Inhibitor in vivo Tool Compound starting from an HSQC-NMR based Fragment Hit
Structural highlights
FunctionPublication Abstract from PubMedActivating mutations in KRAS are the most frequent oncogenic alterations in cancer. The oncogenic hotspot position 12, located at the lip of the switch II pocket, offers a covalent attachment point for KRAS(G12C) inhibitors. To date, KRAS(G12C) inhibitors have been discovered by first covalently binding to the cysteine at position 12 and then optimizing pocket binding. We report on the discovery of the in vivo active KRAS(G12C) inhibitor BI-0474 using a different approach, in which small molecules that bind reversibly to the switch II pocket were identified and then optimized for non-covalent binding using structure-based design. Finally, the Michael acceptor containing warhead was attached. Our approach offers not only an alternative approach to discovering KRAS(G12C) inhibitors but also provides a starting point for the discovery of inhibitors against other oncogenic KRAS mutants. Fragment Optimization of Reversible Binding to the Switch II Pocket on KRAS Leads to a Potent, In Vivo Active KRAS(G12C) Inhibitor.,Broker J, Waterson AG, Smethurst C, Kessler D, Bottcher J, Mayer M, Gmaschitz G, Phan J, Little A, Abbott JR, Sun Q, Gmachl M, Rudolph D, Arnhof H, Rumpel K, Savarese F, Gerstberger T, Mischerikow N, Treu M, Herdeis L, Wunberg T, Gollner A, Weinstabl H, Mantoulidis A, Kramer O, McConnell DB, W Fesik S J Med Chem. 2022 Oct 27. doi: 10.1021/acs.jmedchem.2c01120. PMID:36300829[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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