View source for 6ym5


==Crystal structure of BAY-091 with PIP4K2A==
<StructureSection load='6ym5' size='340' side='right'caption='[[6ym5]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6ym5]] 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=6YM5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6YM5 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]] 2.5&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=OZ5:(2~{R})-2-[[3-cyano-2-[4-(2-fluoranyl-3-methyl-phenyl)phenyl]-1,7-naphthyridin-4-yl]amino]butanoic+acid'>OZ5</scene>, <scene name='pdbligand=PHD:ASPARTYL+PHOSPHATE'>PHD</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</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=6ym5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ym5 OCA], [https://pdbe.org/6ym5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ym5 RCSB], [https://www.ebi.ac.uk/pdbsum/6ym5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ym5 ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/PI42A_HUMAN PI42A_HUMAN] Precursor B-cell acute lymphoblastic leukemia. 
== Function ==
[https://www.uniprot.org/uniprot/PI42A_HUMAN PI42A_HUMAN] Catalyzes the phosphorylation of phosphatidylinositol 5-phosphate (PtdIns5P) on the fourth hydroxyl of the myo-inositol ring, to form phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2). May exert its function by regulating the levels of PtdIns5P, which functions in the cytosol by increasing AKT activity and in the nucleus signals through ING2. May regulate the pool of cytosolic PtdIns5P in response to the activation of tyrosine phosphorylation. May negatively regulate insulin-stimulated glucose uptake by lowering the levels of PtdIns5P. May be involved in thrombopoiesis, and the terminal maturation of megakaryocytes and regulation of their size.<ref>PMID:18364242</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
PIP4K2A is an insufficiently studied type II lipid kinase that catalyzes the conversion of phosphatidylinositol-5-phosphate (PI5P) into phosphatidylinositol 4,5-bisphosphate (PI4,5P2). The involvement of PIP4K2A/B in cancer has been suggested, particularly in the context of p53 mutant/null tumors. PIP4K2A/B depletion has been shown to induce tumor growth inhibition, possibly due to hyperactivation of AKT and reactive oxygen species-mediated apoptosis. Herein, we report the identification of the novel potent and highly selective inhibitors BAY-091 and BAY-297 of the kinase PIP4K2A by high-throughput screening and subsequent structure-based optimization. Cellular target engagement of BAY-091 and BAY-297 was demonstrated using cellular thermal shift assay technology. However, inhibition of PIP4K2A with BAY-091 or BAY-297 did not translate into the hypothesized mode of action and antiproliferative activity in p53-deficient tumor cells. Therefore, BAY-091 and BAY-297 serve as valuable chemical probes to study PIP4K2A signaling and its involvement in pathophysiological conditions such as cancer.

Discovery and Characterization of the Potent and Highly Selective 1,7-Naphthyridine-Based Inhibitors BAY-091 and BAY-297 of the Kinase PIP4K2A.,Wortmann L, Brauer N, Holton SJ, Irlbacher H, Weiske J, Lechner C, Meier R, Karen J, Sioberg CB, Putter V, Christ CD, Ter Laak A, Lienau P, Lesche R, Nicke B, Cheung SH, Bauser M, Haegebarth A, von Nussbaum F, Mumberg D, Lemos C J Med Chem. 2021 Nov 11;64(21):15883-15911. doi: 10.1021/acs.jmedchem.1c01245., Epub 2021 Oct 26. PMID:34699202<ref>PMID:34699202</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6ym5" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Bauser M]]
[[Category: Braeuer N]]
[[Category: Christ C]]
[[Category: Haegebarth A]]
[[Category: Holton SJ]]
[[Category: Irlbacher H]]
[[Category: Lechner C]]
[[Category: Lemos C]]
[[Category: Lesche R]]
[[Category: Lienau P]]
[[Category: Meier R]]
[[Category: Mumberg D]]
[[Category: Nicke B]]
[[Category: Puetter V]]
[[Category: Weiske J]]
[[Category: Wortmann L]]
[[Category: Ter Laak T]]
[[Category: Von Nussbaum F]]