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==Discovery of dihydrothieno- and dihydrofuropyrimidines as potent pan Akt inhibitors==
==Discovery of dihydrothieno- and dihydrofuropyrimidines as potent pan Akt inhibitors==
<StructureSection load='3ow3' size='340' side='right' caption='[[3ow3]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
<StructureSection load='3ow3' size='340' side='right'caption='[[3ow3]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[3ow3]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. 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 [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3OW3 FirstGlance]. <br>
<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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><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></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.9&#8491;</td></tr>
<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></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='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3ow4|3ow4]]</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>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Prkaca, Pkaca ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice])</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/cAMP-dependent_protein_kinase cAMP-dependent protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.11 2.7.11.11] </span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3ow3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ow3 OCA], [http://pdbe.org/3ow3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3ow3 RCSB], [http://www.ebi.ac.uk/pdbsum/3ow3 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3ow3 ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/KAPCA_MOUSE KAPCA_MOUSE]] Phosphorylates a large number of substrates in the cytoplasm and the nucleus. Regulates the abundance of compartmentalized pools of its regulatory subunits through phosphorylation of PJA2 which binds and ubiquitinates these subunits, leading to their subsequent proteolysis. Phosphorylates CDC25B, ABL1, NFKB1, CLDN3, PSMC5/RPT6, PJA2, RYR2, RORA, TRPC1 and VASP. RORA is activated by phosphorylation. Required for glucose-mediated adipogenic differentiation increase and osteogenic differentiation inhibition from osteoblasts. Involved in the regulation of platelets in response to thrombin and collagen; maintains circulating platelets in a resting state by phosphorylating proteins in numerous platelet inhibitory pathways when in complex with NF-kappa-B (NFKB1 and NFKB2) and I-kappa-B-alpha (NFKBIA), but thrombin and collagen disrupt these complexes and free active PRKACA stimulates platelets and leads to platelet aggregation by phosphorylating VASP. Prevents the antiproliferative and anti-invasive effects of alpha-difluoromethylornithine in breast cancer cells when activated. RYR2 channel activity is potentiated by phosphorylation in presence of luminal Ca(2+), leading to reduced amplitude and increased frequency of store overload-induced Ca(2+) release (SOICR) characterized by an increased rate of Ca(2+) release and propagation velocity of spontaneous Ca(2+) waves, despite reduced wave amplitude and resting cytosolic Ca(2+). TRPC1 activation by phosphorylation promotes Ca(2+) influx, essential for the increase in permeability induced by thrombin in confluent endothelial monolayers. PSMC5/RPT6 activation by phosphorylation stimulates proteasome. Regulates negatively tight junction (TJs) in ovarian cancer cells via CLDN3 phosphorylation. NFKB1 phosphorylation promotes NF-kappa-B p50-p50 DNA binding. Involved in embryonic development by down-regulating the Hedgehog (Hh) signaling pathway that determines embryo pattern formation and morphogenesis. Isoform 2 phosphorylates and activates ABL1 in sperm flagellum to promote spermatozoa capacitation. Prevents meiosis resumption in prophase-arrested oocytes via CDC25B inactivation by phosphorylation. May also regulate rapid eye movement (REM) sleep in the pedunculopontine tegmental (PPT).<ref>PMID:15340140</ref> <ref>PMID:19223768</ref> <ref>PMID:19560455</ref>  [[http://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.  
[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;">
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
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==See Also==
==See Also==
*[[CAMP-dependent protein kinase|CAMP-dependent protein kinase]]
*[[CAMP-dependent protein kinase 3D structures|CAMP-dependent protein kinase 3D structures]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Lk3 transgenic mice]]
[[Category: Large Structures]]
[[Category: CAMP-dependent protein kinase]]
[[Category: Mus musculus]]
[[Category: Brandhuber, B J]]
[[Category: Brandhuber BJ]]
[[Category: Dizon, F]]
[[Category: Dizon F]]
[[Category: Vigers, G P.A]]
[[Category: Vigers GPA]]
[[Category: Wu, W]]
[[Category: Wu W]]
[[Category: Cyclic-amp dependent protein kinase]]
[[Category: Transferase-transferase inhibitor complex]]

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

3ow3 is a 2 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.9Å
Ligands:, ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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.

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[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ 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. Discovery of dihydrothieno- and dihydrofuropyrimidines as potent pan Akt inhibitors. Bioorg Med Chem Lett. 2010 Dec 1;20(23):7037-41. Epub 2010 Sep 29. PMID:20971641 doi:10.1016/j.bmcl.2010.09.112

3ow3, resolution 1.90Å

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