View source for 7pqv


==MEK1 IN COMPLEX WITH COMPOUND 7==
<StructureSection load='7pqv' size='340' side='right'caption='[[7pqv]], [[Resolution|resolution]] 2.13&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7PQV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7PQV 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]] 2.13&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=80C:8-(2-chloranyl-4-methoxy-phenyl)-7-fluoranyl-1-piperidin-4-yl-imidazo[4,5-c]quinoline'>80C</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</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=7pqv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7pqv OCA], [https://pdbe.org/7pqv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7pqv RCSB], [https://www.ebi.ac.uk/pdbsum/7pqv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7pqv ProSAT]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Mutations in MEK1/2 have been described as a resistance mechanism to BRAF/MEK inhibitor treatment. We report the discovery of a novel ATP-competitive MEK1/2 inhibitor with efficacy in wildtype (WT) and mutant MEK12 models. Starting from a HTS hit, we obtained selective, cellularly active compounds that showed equipotent inhibition of WT MEK1/2 and a panel of MEK1/2 mutant cell lines. Using a structure-based approach, the optimization addressed the liabilities by systematic analysis of molecular matched pairs (MMPs) and ligand conformation. Addition of only three heavy atoms to early tool compound 6 removed Cyp3A4 liabilities and increased the cellular potency by 100-fold, while reducing log P by 5 units. Profiling of MAP855, compound 30, in pharmacokinetic-pharmacodynamic and efficacy studies in BRAF-mutant models showed comparable efficacy to clinical MEK1/2 inhibitors. Compound 30 is a novel highly potent and selective MEK1/2 kinase inhibitor with equipotent inhibition of WT and mutant MEK1/2, whose drug-like properties allow further investigation in the mutant MEK setting upon BRAF/MEK therapy.

Discovery of MAP855, an Efficacious and Selective MEK1/2 Inhibitor with an ATP-Competitive Mode of Action.,Poddutoori R, Aardalen K, Aithal K, Barahagar SS, Belliappa C, Bock M, Chelur S, Gerken A, Gopinath S, Gruenenfelder B, Kiffe M, Krishnaswami M, Langowski J, Madapa S, Narayanan K, Pandit C, Panigrahi SK, Perrone M, Potakamuri RK, Ramachandra M, Ramanathan A, Ramos R, Sager E, Samajdar S, Subramanya HS, Thimmasandra DS, Venetsanakos E, Mobitz H J Med Chem. 2022 Mar 10;65(5):4350-4366. doi: 10.1021/acs.jmedchem.1c02192. Epub , 2022 Feb 23. PMID:35195996<ref>PMID:35195996</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7pqv" style="background-color:#fffaf0;"></div>

==See Also==
*[[Mitogen-activated protein kinase kinase 3D structures|Mitogen-activated protein kinase kinase 3D structures]]
== References ==
<references/>
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</StructureSection>
[[Category: Large Structures]]
[[Category: Moebitz H]]