3ow3: Difference between revisions
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< | ==Discovery of dihydrothieno- and dihydrofuropyrimidines as potent pan Akt inhibitors== | ||
<StructureSection load='3ow3' size='340' side='right'caption='[[3ow3]], [[Resolution|resolution]] 1.90Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3ow3]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3OW3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3OW3 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]] 1.9Å</td></tr> | |||
- | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene>, <scene name='pdbligand=SMY:(2R)-3-(1H-INDOL-3-YL)-1-{4-[(5S)-5-METHYL-5,7-DIHYDROTHIENO[3,4-D]PYRIMIDIN-4-YL]PIPERAZIN-1-YL}-1-OXOPROPAN-2-AMINE'>SMY</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</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=3ow3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ow3 OCA], [https://pdbe.org/3ow3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3ow3 RCSB], [https://www.ebi.ac.uk/pdbsum/3ow3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3ow3 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/IPKA_MOUSE IPKA_MOUSE] Extremely potent competitive inhibitor of cAMP-dependent protein kinase activity, this protein interacts with the catalytic subunit of the enzyme after the cAMP-induced dissociation of its regulatory chains. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Herein we report the discovery and synthesis of a novel series of dihydrothieno- and dihydrofuropyrimidines (2 and 3) as potent pan Akt inhibitors. Utilizing previous SAR and analysis of the amino acid sequences in the binding site we have designed inhibitors displaying increased PKA and general kinase selectivity with improved tolerability compared to the progenitor pyrrolopyrimidine (1). A representative dihydrothieno compound (34) was advanced into a PC3-NCI prostate mouse tumor model in which it demonstrated a dose-dependent reduction in tumor growth and stasis when dosed orally daily at 200mg/kg. | |||
Discovery of dihydrothieno- and dihydrofuropyrimidines as potent pan Akt inhibitors.,Bencsik JR, Xiao D, Blake JF, Kallan NC, Mitchell IS, Spencer KL, Xu R, Gloor SL, Martinson M, Risom T, Woessner RD, Dizon F, Wu WI, Vigers GP, Brandhuber BJ, Skelton NJ, Prior WW, Murray LJ Bioorg Med Chem Lett. 2010 Dec 1;20(23):7037-41. Epub 2010 Sep 29. PMID:20971641<ref>PMID:20971641</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 3ow3" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[CAMP-dependent protein kinase 3D structures|CAMP-dependent protein kinase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
== | [[Category: Large Structures]] | ||
== | |||
< | |||
[[Category: Mus musculus]] | [[Category: Mus musculus]] | ||
[[Category: Brandhuber BJ]] | |||
[[Category: Brandhuber | [[Category: Dizon F]] | ||
[[Category: Dizon | [[Category: Vigers GPA]] | ||
[[Category: Vigers | [[Category: Wu W]] | ||
[[Category: Wu | |||
Latest revision as of 05:14, 21 November 2024
Discovery of dihydrothieno- and dihydrofuropyrimidines as potent pan Akt inhibitorsDiscovery of dihydrothieno- and dihydrofuropyrimidines as potent pan Akt inhibitors
Structural highlights
FunctionIPKA_MOUSE Extremely potent competitive inhibitor of cAMP-dependent protein kinase activity, this protein interacts with the catalytic subunit of the enzyme after the cAMP-induced dissociation of its regulatory chains. Publication Abstract from PubMedHerein we report the discovery and synthesis of a novel series of dihydrothieno- and dihydrofuropyrimidines (2 and 3) as potent pan Akt inhibitors. Utilizing previous SAR and analysis of the amino acid sequences in the binding site we have designed inhibitors displaying increased PKA and general kinase selectivity with improved tolerability compared to the progenitor pyrrolopyrimidine (1). A representative dihydrothieno compound (34) was advanced into a PC3-NCI prostate mouse tumor model in which it demonstrated a dose-dependent reduction in tumor growth and stasis when dosed orally daily at 200mg/kg. Discovery of dihydrothieno- and dihydrofuropyrimidines as potent pan Akt inhibitors.,Bencsik JR, Xiao D, Blake JF, Kallan NC, Mitchell IS, Spencer KL, Xu R, Gloor SL, Martinson M, Risom T, Woessner RD, Dizon F, Wu WI, Vigers GP, Brandhuber BJ, Skelton NJ, Prior WW, Murray LJ Bioorg Med Chem Lett. 2010 Dec 1;20(23):7037-41. Epub 2010 Sep 29. PMID:20971641[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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