2bpm: Difference between revisions

← Older edit Newer edit →

Revision as of 17:05, 20 March 2008

File:2bpm.gif

, resolution 2.40Å

Sites:

Ligands:

and

Activity:

Transferred entry: 2.7.11.1, with EC number 2.7.1.37

Coordinates:

save as pdb, mmCIF, xml

STRUCTURE OF CDK2-CYCLIN A WITH PHA-630529

OverviewOverview

Inhibitors of cyclin-dependent kinases (CDK) such as CDK2/cyclin A-E are currently undergoing clinical trials to verify their potential as new anticancer agents. In a previous article we described the lead discovery process of a 3-aminopyrazole class of CDK2/cyclin A-E inhibitors. The endpoint of this process was PNU-292137, a compound endowed with in vivo antitumor activity in a mouse tumor xenograft model. We optimized this lead compound to improve some physicochemical properties, notably solubility and plasma protein binding. This lead optimization process brought us to the discovery of (2S)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-[4-(2-oxo-1-pyrrolidinyl)phenyl]p ropanamide (PHA-533533, 13), a compound with a balanced activity vs druglike profile. Compound 13 inhibited CDK2/cyclin A with a K(i) of 31 nM, counteracting tumor cell proliferation of different cell lines with an IC(50) in the submicromolar range. Solubility was improved more than 10 times over the starting lead, while plasma protein binding was decreased from 99% to 74%. With exploitation of this globally enhanced in vitro profile, 13 was more active than PNU-292137 in vivo in the A2780 xenograft model showing a tumor growth inhibition of 70%. Proof of mechanism of action was obtained in vivo by immunohistochemical analysis of tumor slices of 13-treated vs untreated animals.

About this StructureAbout this Structure

2BPM is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.

ReferenceReference

3-Aminopyrazole inhibitors of CDK2/cyclin A as antitumor agents. 2. Lead optimization., Pevarello P, Brasca MG, Orsini P, Traquandi G, Longo A, Nesi M, Orzi F, Piutti C, Sansonna P, Varasi M, Cameron A, Vulpetti A, Roletto F, Alzani R, Ciomei M, Albanese C, Pastori W, Marsiglio A, Pesenti E, Fiorentini F, Bischoff JR, Mercurio C, J Med Chem. 2005 Apr 21;48(8):2944-56. PMID:15828833

Page seeded by OCA on Thu Mar 20 16:05:00 2008

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

@@ Line 1: / Line 1: @@
-[[Image:2bpm.gif|left|200px]]<br /><applet load="2bpm" size="350" color="white" frame="true" align="right" spinBox="true"
+[[Image:2bpm.gif|left|200px]]
-caption="2bpm, resolution 2.40&Aring;" />
-'''STRUCTURE OF CDK2-CYCLIN A WITH PHA-630529'''<br />
+ {{Structure
+|PDB= 2bpm |SIZE=350|CAPTION= <scene name='initialview01'>2bpm</scene>, resolution 2.40&Aring;
+|SITE= <scene name='pdbsite=AC1:So4+Binding+Site+For+Chain+D'>AC1</scene>
+|LIGAND= <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene> and <scene name='pdbligand=529:(2S)-N-[(3Z)-5-CYCLOPROPYL-3H-PYRAZOL-3-YLIDENE]-2-[4-(2-OXOIMIDAZOLIDIN-1-YL)PHENYL]PROPANAMIDE'>529</scene>
+|ACTIVITY= [http://en.wikipedia.org/wiki/Transferred_entry:_2.7.11.1 Transferred entry: 2.7.11.1], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.37 2.7.1.37]
+|GENE=
+}}
+'''STRUCTURE OF CDK2-CYCLIN A WITH PHA-630529'''
 ==Overview==
@@ Line 7: / Line 16: @@
 ==About this Structure==
-BPM is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=SO4:'>SO4</scene> and <scene name='pdbligand=529:'>529</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Transferred_entry:_2.7.11.1 Transferred entry: 2.7.11.1], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.37 2.7.1.37] Known structural/functional Site: <scene name='pdbsite=AC1:So4+Binding+Site+For+Chain+D'>AC1</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2BPM OCA].
+BPM is a [[Protein complex]] structure of sequences 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=2BPM OCA].
 ==Reference==
--Aminopyrazole inhibitors of CDK2/cyclin A as antitumor agents. 2. Lead optimization., Pevarello P, Brasca MG, Orsini P, Traquandi G, Longo A, Nesi M, Orzi F, Piutti C, Sansonna P, Varasi M, Cameron A, Vulpetti A, Roletto F, Alzani R, Ciomei M, Albanese C, Pastori W, Marsiglio A, Pesenti E, Fiorentini F, Bischoff JR, Mercurio C, J Med Chem. 2005 Apr 21;48(8):2944-56. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=15828833 15828833]
+-Aminopyrazole inhibitors of CDK2/cyclin A as antitumor agents. 2. Lead optimization., Pevarello P, Brasca MG, Orsini P, Traquandi G, Longo A, Nesi M, Orzi F, Piutti C, Sansonna P, Varasi M, Cameron A, Vulpetti A, Roletto F, Alzani R, Ciomei M, Albanese C, Pastori W, Marsiglio A, Pesenti E, Fiorentini F, Bischoff JR, Mercurio C, J Med Chem. 2005 Apr 21;48(8):2944-56. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/15828833 15828833]
 [[Category: Homo sapiens]]
 [[Category: Protein complex]]
@@ Line 46: / Line 55: @@
 [[Category: transferase]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:40:16 2008''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 16:05:00 2008''