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==Structure-guided optimization of a novel class of ASK1 inhibitors with increased sp3 character and an exquisite selectivity profile==
<StructureSection load='6xih' size='340' side='right'caption='[[6xih]], [[Resolution|resolution]] 2.65&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6xih]] 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=6XIH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6XIH 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]] 2.65&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=V3S:(2R)-N-{6-[4-(propan-2-yl)-4H-1,2,4-triazol-3-yl]pyridin-2-yl}oxane-2-carboxamide'>V3S</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=6xih FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6xih OCA], [https://pdbe.org/6xih PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6xih RCSB], [https://www.ebi.ac.uk/pdbsum/6xih PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6xih ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/M3K5_HUMAN M3K5_HUMAN] Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. Plays an important role in the cascades of cellular responses evoked by changes in the environment. Mediates signaling for determination of cell fate such as differentiation and survival. Plays a crucial role in the apoptosis signal transduction pathway through mitochondria-dependent caspase activation. MAP3K5/ASK1 is required for the innate immune response, which is essential for host defense against a wide range of pathogens. Mediates signal transduction of various stressors like oxidative stress as well as by receptor-mediated inflammatory signals, such as the tumor necrosis factor (TNF) or lipopolysaccharide (LPS). Once activated, acts as an upstream activator of the MKK/JNK signal transduction cascade and the p38 MAPK signal transduction cascade through the phosphorylation and activation of several MAP kinase kinases like MAP2K4/SEK1, MAP2K3/MKK3, MAP2K6/MKK6 and MAP2K7/MKK7. These MAP2Ks in turn activate p38 MAPKs and c-jun N-terminal kinases (JNKs). Both p38 MAPK and JNKs control the transcription factors activator protein-1 (AP-1).<ref>PMID:8940179</ref> <ref>PMID:8974401</ref> <ref>PMID:9564042</ref> <ref>PMID:9774977</ref> <ref>PMID:10411906</ref> <ref>PMID:10849426</ref> <ref>PMID:10688666</ref> <ref>PMID:11689443</ref> <ref>PMID:11029458</ref> <ref>PMID:11154276</ref> <ref>PMID:14749717</ref> <ref>PMID:11920685</ref> <ref>PMID:12697749</ref> <ref>PMID:15023544</ref> <ref>PMID:14688258</ref> <ref>PMID:16129676</ref> <ref>PMID:17220297</ref> 
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== Publication Abstract from PubMed ==
Apoptosis Signal-Regulating Kinase-1 (ASK1) is a known member of the Mitogen-Activated Protein Kinase Kinase Kinase (MAP3K) family and upon stimulation will activate the p38- and JNK-pathways leading to cardiac apoptosis, fibrosis, and hypertrophy. Using Structure-Based Drug Design (SBDD) in parallel with deconstruction of a published compound, a novel series of ASK1 inhibitors was optimized, which incorporated a saturated heterocycle proximal to the hinge-binding motif. This yielded a unique chemical series with excellent selectivity across the broader kinome, and desirable drug-like properties. The lead compound (10) is highly soluble and permeable, and exhibits a cellular EC50 = 24 nM and Kd &lt; 1 nM. Of the 350 kinases tested, 10 has an IC50 &lt;/= 500 nM for only eight of them. This paper will describe the design hypotheses behind this series, key data points during the optimization phase, as well as a possible structural rationale for the kinome selectivity. Based on crystallographic data, the presence of an aliphatic cycle adjacent to the hinge-binder in the active site of the protein kinase showed up in &lt;1% of the &gt;5000 structures in the Protein Data Bank, potentially conferring the selectivity seen in this series.

Structure-guided optimization of a novel class of ASK1 inhibitors with increased sp(3) character and an exquisite selectivity profile.,Bigi-Botterill SV, Ivetac A, Bradshaw EL, Cole D, Dougan DR, Ermolieff J, Halkowycz P, Johnson B, McBride C, Pickens J, Sabat M, Swann S Bioorg Med Chem Lett. 2020 Sep 1;30(17):127405. doi: 10.1016/j.bmcl.2020.127405. , Epub 2020 Jul 12. PMID:32738982<ref>PMID:32738982</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6xih" style="background-color:#fffaf0;"></div>

==See Also==
*[[Mitogen-activated protein kinase kinase kinase|Mitogen-activated protein kinase kinase kinase]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Dougan DR]]