View source for 8wjy


==PKMYT1_Cocrystal_Cpd 4==
<StructureSection load='8wjy' size='340' side='right'caption='[[8wjy]], [[Resolution|resolution]] 1.88&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8wjy]] is a 1 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=8WJY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8WJY 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]] 1.88&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=W9X:[6-azanyl-5-(2,6-dimethyl-3-oxidanyl-phenyl)-2,3-dimethyl-pyrrolo[2,3-b]pyrazin-7-yl]-(6,7-dihydro-4~{H}-pyrazolo[1,5-a]pyrazin-5-yl)methanone'>W9X</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=8wjy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8wjy OCA], [https://pdbe.org/8wjy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8wjy RCSB], [https://www.ebi.ac.uk/pdbsum/8wjy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8wjy ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/PMYT1_HUMAN PMYT1_HUMAN] Acts as a negative regulator of entry into mitosis (G2 to M transition) by phosphorylation of the CDK1 kinase specifically when CDK1 is complexed to cyclins. Mediates phosphorylation of CDK1 predominantly on 'Thr-14'. Also involved in Golgi fragmentation. May be involved in phosphorylation of CDK1 on 'Tyr-15' to a lesser degree, however tyrosine kinase activity is unclear and may be indirect. May be a downstream target of Notch signaling pathway during eye development.<ref>PMID:9001210</ref> <ref>PMID:10373560</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Breast and gynecological cancers are among the leading causes of death in women worldwide, illustrating the urgent need for innovative treatment options. We identified MYT1 as a promising new therapeutic target for breast and gynecological cancer using PandaOmics, an AI-driven target discovery platform. The synthetic lethal relationship of MYT1 in tumor cell lines with CCNE1 amplification enhanced this rationale. Through structure-based drug design, we developed a series of novel, potent, and highly selective inhibitors specifically targeting MYT1. Importantly, our lead compound, featuring a tetrahydropyrazolopyrazine ring, exhibits remarkable selectivity over WEE1, a related kinase associated with bone marrow suppression upon inhibition. Optimization of potency and physical properties resulted in the discovery of compound 21, a novel MYT1 inhibitor, exhibiting optimal pharmacokinetic properties and promising in vivo antitumor efficacy.

Discovery of Tetrahydropyrazolopyrazine Derivatives as Potent and Selective MYT1 Inhibitors for the Treatment of Cancer.,Wang Y, Wang C, Liu T, Qi H, Chen S, Cai X, Zhang M, Aliper A, Ren F, Ding X, Zhavoronkov A J Med Chem. 2024 Jan 11;67(1):420-432. doi: 10.1021/acs.jmedchem.3c01476. Epub , 2023 Dec 26. PMID:38146659<ref>PMID:38146659</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8wjy" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Aliper A]]
[[Category: Cai X]]
[[Category: Chen S]]
[[Category: Ding X]]
[[Category: Liu T]]
[[Category: Qi H]]
[[Category: Ren F]]
[[Category: Wang C]]
[[Category: Wang Y]]
[[Category: Zhang M]]
[[Category: Zhavoronkov A]]