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| [[Image:2io6.jpg|left|200px]] | | {{Seed}} |
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| {{STRUCTURE_2io6| PDB=2io6 | SCENE= }} | | {{STRUCTURE_2io6| PDB=2io6 | SCENE= }} |
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| '''Wee1 kinase complexed with inhibitor PD330961'''
| | ===Wee1 kinase complexed with inhibitor PD330961=== |
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| ==Overview==
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| A series of N-6 substituted 9-hydroxy-4-phenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-diones were prepared from N-substituted (5-methoxyphenyl)ethenylindoles. The target compounds were tested for their ability to inhibit the G2/M cell cycle checkpoint kinases, Wee1 and Chk1. Analogues with neutral or cationic N-6 side chains were potent dual inhibitors. Acidic side chains provided potent (average IC(50) 0.057muM) and selective (average ratio 223-fold) Wee1 inhibition. Co-crystal structures of inhibitors bound to Wee1 show that the pyrrolo[3,4-c]carbazole scaffold binds in the ATP-binding site, with N-6 substituents involved in H-bonding to conserved water molecules. HT-29 cells treated with doxorubicin and then target compounds demonstrate an active Cdc2/cyclin B complex, inhibition of the doxorubicin-induced phosphorylation of tyrosine 15 of Cdc2 and abrogation of the G2 checkpoint.
| | The line below this paragraph, {{ABSTRACT_PUBMED_17869387}}, adds the Publication Abstract to the page |
| | (as it appears on PubMed at http://www.pubmed.gov), where 17869387 is the PubMed ID number. |
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| | {{ABSTRACT_PUBMED_17869387}} |
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| ==About this Structure== | | ==About this Structure== |
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| [[Category: Protein-inhibitor complex]] | | [[Category: Protein-inhibitor complex]] |
| [[Category: Transferase]] | | [[Category: Transferase]] |
| ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 07:42:42 2008'' | | |
| | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jul 2 20:54:48 2008'' |