3rwp: Difference between revisions
Jump to navigation
Jump to search
No edit summary |
No edit summary |
||
| Line 1: | Line 1: | ||
[[ | ==Discovery of a Novel, Potent and Selective Inhibitor of 3-Phosphoinositide Dependent Kinase (PDK1)== | ||
<StructureSection load='3rwp' size='340' side='right' caption='[[3rwp]], [[Resolution|resolution]] 1.92Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3rwp]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3RWP OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3RWP FirstGlance]. <br> | |||
</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ABQ:[4-AMINO-7-(PROPAN-2-YL)-7H-PYRROLO[2,3-D]PYRIMIDIN-5-YL](6-{[(3S,4R)-4-(4-FLUOROPHENYL)TETRAHYDROFURAN-3-YL]AMINO}PYRAZIN-2-YL)METHANONE'>ABQ</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene><br> | |||
<tr><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene></td></tr> | |||
<tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3sc1|3sc1]], [[3rwq|3rwq]]</td></tr> | |||
<tr><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PDPK1, PDK1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr> | |||
<tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </span></td></tr> | |||
<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3rwp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3rwp OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3rwp RCSB], [http://www.ebi.ac.uk/pdbsum/3rwp PDBsum]</span></td></tr> | |||
<table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Analogs substituted with various amines at the 6-position of the pyrazine ring on (4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-pyrazin-2-yl-methano ne were discovered as potent and selective inhibitors of PDK1 with potential as anti-cancer agents. An early lead with 2-pyridine-3-yl-ethylamine as the pyrazine substituent showed moderate potency and selectivity. Structure-based drug design led to improved potency and selectivity against PI3Kalpha through a combination of cyclizing the ethylene spacer into a saturated, five-membered ring and by substitution on the 4-position of the aryl ring with a fluorine. ADME properties were improved by lowering the lipophilicity with heteroatom replacements in the saturated, five-membered ring. The optimized analogs have a PDK1 Ki of 1 nM and >100-fold selectivity against PI3K/AKT-pathway kinases. The cellular potency of these analogs was assessed by the inhibition of AKT phosphorylation (T308) and by their anti-proliferation activity against a number of tumor cell lines. | |||
Discovery of Novel, Potent and Selective Inhibitors of 3-Phosphoinositide-Dependent Kinase (PDK1).,Murphy ST, Bailey S, Burke BJ, Chappie TA, Ferre R, Greasley S, Hickey MJ, Humphrey J, Kablaoui N, Kath J, Kazmirski S, Kraus M, Kupchinskey S, Li J, Marx MA, Richter D, Tanis SP, Tran K, Vernier W, Alton G, Baxi SM, Ermolieff J, Lingardo L, Xie Z, Yin MJ, Yu XH J Med Chem. 2011 Oct 31. PMID:22040023<ref>PMID:22040023</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
==See Also== | |||
*[[3-phosphoinositide-dependent protein kinase 1|3-phosphoinositide-dependent protein kinase 1]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
== | |||
[[ | |||
== | |||
< | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Non-specific serine/threonine protein kinase]] | [[Category: Non-specific serine/threonine protein kinase]] | ||
Revision as of 07:53, 5 June 2014
Discovery of a Novel, Potent and Selective Inhibitor of 3-Phosphoinositide Dependent Kinase (PDK1)Discovery of a Novel, Potent and Selective Inhibitor of 3-Phosphoinositide Dependent Kinase (PDK1)
Structural highlights
Publication Abstract from PubMedAnalogs substituted with various amines at the 6-position of the pyrazine ring on (4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-pyrazin-2-yl-methano ne were discovered as potent and selective inhibitors of PDK1 with potential as anti-cancer agents. An early lead with 2-pyridine-3-yl-ethylamine as the pyrazine substituent showed moderate potency and selectivity. Structure-based drug design led to improved potency and selectivity against PI3Kalpha through a combination of cyclizing the ethylene spacer into a saturated, five-membered ring and by substitution on the 4-position of the aryl ring with a fluorine. ADME properties were improved by lowering the lipophilicity with heteroatom replacements in the saturated, five-membered ring. The optimized analogs have a PDK1 Ki of 1 nM and >100-fold selectivity against PI3K/AKT-pathway kinases. The cellular potency of these analogs was assessed by the inhibition of AKT phosphorylation (T308) and by their anti-proliferation activity against a number of tumor cell lines. Discovery of Novel, Potent and Selective Inhibitors of 3-Phosphoinositide-Dependent Kinase (PDK1).,Murphy ST, Bailey S, Burke BJ, Chappie TA, Ferre R, Greasley S, Hickey MJ, Humphrey J, Kablaoui N, Kath J, Kazmirski S, Kraus M, Kupchinskey S, Li J, Marx MA, Richter D, Tanis SP, Tran K, Vernier W, Alton G, Baxi SM, Ermolieff J, Lingardo L, Xie Z, Yin MJ, Yu XH J Med Chem. 2011 Oct 31. PMID:22040023[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
|
| ||||||||||||||||||||||||