2a4z: Difference between revisions

Revision as of 17:23, 21 February 2008

Crystal Structure of human PI3Kgamma complexed with AS604850

OverviewOverview

Phosphoinositide 3-kinases (PI3K) have long been considered promising drug targets for the treatment of inflammatory and autoimmune disorders as well as cancer and cardiovascular diseases. But the lack of specificity, isoform selectivity and poor biopharmaceutical profile of PI3K inhibitors have so far hampered rigorous disease-relevant target validation. Here we describe the identification and development of specific, selective and orally active small-molecule inhibitors of PI3Kgamma (encoded by Pik3cg). We show that Pik3cg(-/-) mice are largely protected in mouse models of rheumatoid arthritis; this protection correlates with defective neutrophil migration, further validating PI3Kgamma as a therapeutic target. We also describe that oral treatment with a PI3Kgamma inhibitor suppresses the progression of joint inflammation and damage in two distinct mouse models of rheumatoid arthritis, reproducing the protective effects shown by Pik3cg(-/-) mice. Our results identify selective PI3Kgamma inhibitors as potential therapeutic molecules for the treatment of chronic inflammatory disorders such as rheumatoid arthritis.

About this StructureAbout this Structure

2A4Z is a Single protein structure of sequence from Homo sapiens with as ligand. Active as Phosphatidylinositol-4,5-bisphosphate 3-kinase, with EC number 2.7.1.153 Full crystallographic information is available from OCA.

ReferenceReference

Blockade of PI3Kgamma suppresses joint inflammation and damage in mouse models of rheumatoid arthritis., Camps M, Ruckle T, Ji H, Ardissone V, Rintelen F, Shaw J, Ferrandi C, Chabert C, Gillieron C, Francon B, Martin T, Gretener D, Perrin D, Leroy D, Vitte PA, Hirsch E, Wymann MP, Cirillo R, Schwarz MK, Rommel C, Nat Med. 2005 Sep;11(9):936-43. Epub 2005 Aug 28. PMID:16127437

Page seeded by OCA on Thu Feb 21 16:23:38 2008

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OCA

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-[[Image:2a4z.gif|left|200px]]<br />
+[[Image:2a4z.gif|left|200px]]<br /><applet load="2a4z" size="350" color="white" frame="true" align="right" spinBox="true"
-<applet load="2a4z" size="450" color="white" frame="true" align="right" spinBox="true"
 caption="2a4z, resolution 2.900&Aring;" />
 '''Crystal Structure of human PI3Kgamma complexed with AS604850'''<br />
 ==Overview==
-Phosphoinositide 3-kinases (PI3K) have long been considered promising drug, targets for the treatment of inflammatory and autoimmune disorders as well, as cancer and cardiovascular diseases. But the lack of specificity, isoform selectivity and poor biopharmaceutical profile of PI3K inhibitors, have so far hampered rigorous disease-relevant target validation. Here we, describe the identification and development of specific, selective and, orally active small-molecule inhibitors of PI3Kgamma (encoded by Pik3cg)., We show that Pik3cg(-/-) mice are largely protected in mouse models of, rheumatoid arthritis; this protection correlates with defective neutrophil, migration, further validating PI3Kgamma as a therapeutic target. We also, describe that oral treatment with a PI3Kgamma inhibitor suppresses the, progression of joint inflammation and damage in two distinct mouse models, of rheumatoid arthritis, reproducing the protective effects shown by, Pik3cg(-/-) mice. Our results identify selective PI3Kgamma inhibitors as, potential therapeutic molecules for the treatment of chronic inflammatory, disorders such as rheumatoid arthritis.
+Phosphoinositide 3-kinases (PI3K) have long been considered promising drug targets for the treatment of inflammatory and autoimmune disorders as well as cancer and cardiovascular diseases. But the lack of specificity, isoform selectivity and poor biopharmaceutical profile of PI3K inhibitors have so far hampered rigorous disease-relevant target validation. Here we describe the identification and development of specific, selective and orally active small-molecule inhibitors of PI3Kgamma (encoded by Pik3cg). We show that Pik3cg(-/-) mice are largely protected in mouse models of rheumatoid arthritis; this protection correlates with defective neutrophil migration, further validating PI3Kgamma as a therapeutic target. We also describe that oral treatment with a PI3Kgamma inhibitor suppresses the progression of joint inflammation and damage in two distinct mouse models of rheumatoid arthritis, reproducing the protective effects shown by Pik3cg(-/-) mice. Our results identify selective PI3Kgamma inhibitors as potential therapeutic molecules for the treatment of chronic inflammatory disorders such as rheumatoid arthritis.
 ==About this Structure==
-A4Z is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with BYM as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Phosphatidylinositol-4,5-bisphosphate_3-kinase Phosphatidylinositol-4,5-bisphosphate 3-kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.153 2.7.1.153] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2A4Z OCA].
+A4Z is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=BYM:'>BYM</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Phosphatidylinositol-4,5-bisphosphate_3-kinase Phosphatidylinositol-4,5-bisphosphate 3-kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.153 2.7.1.153] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2A4Z OCA].
 ==Reference==
@@ Line 31: / Line 30: @@
 [[Category: Rommel, C.]]
 [[Category: Ruckle, T.]]
-[[Category: Schwarz, M.K.]]
+[[Category: Schwarz, M K.]]
 [[Category: Shaw, J.]]
-[[Category: Vitte, P.A.]]
+[[Category: Vitte, P A.]]
-[[Category: Wymann, M.P.]]
+[[Category: Wymann, M P.]]
 [[Category: BYM]]
 [[Category: pi3kg]]
 [[Category: protein-inhibitor complex]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 20:46:20 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:23:38 2008''