2IN6

Wee1 kinase complex with inhibitor PD311839

Summary for 2IN6

• Entry DOI: 10.2210/pdb2in6/pdb
• Related: 1X8B
• Descriptor: Wee1-like protein kinase, 3-(9-HYDROXY-1,3-DIOXO-4-PHENYL-2,3-DIHYDROPYRROLO[3,4-C]CARBAZOL-6(1H)-YL)PROPANOIC ACID (3 entities in total)
• Functional Keywords: protein-inhibitor complex, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus: P30291
• Total number of polymer chains: 1
• Total formula weight: 32769.22

Authors

Squire, C.J.,Dickson, J.M.,Ivanovic, I.,Baker, E.N. (deposition date: 2006-10-05, release date: 2007-09-18, Last modification date: 2023-08-30)

Primary citation

Smaill, J.B.,Baker, E.N.,Booth, R.J.,Bridges, A.J.,Dickson, J.M.,Dobrusin, E.M.,Ivanovic, I.,Kraker, A.J.,Lee, H.H.,Lunney, E.A.,Ortwine, D.F.,Palmer, B.D.,Quin, J.,Squire, C.J.,Thompson, A.M.,Denny, W.A.
Synthesis and structure-activity relationships of N-6 substituted analogues of 9-hydroxy-4-phenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-diones as inhibitors of Wee1 and Chk1 checkpoint kinases.
Eur.J.Med.Chem., 43:1276-1296, 2008

PubMed Abstract: 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) 0.057 microM) 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.

PubMed: 17869387
DOI: 10.1016/j.ejmech.2007.07.016

Experimental method

X-RAY DIFFRACTION (1.9 Å)