Synthesis and structure-activity relationships of soluble 8-substituted 4-(2-chlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-1,3(2H,6H)-diones as inhibitors of the Wee1 and Chk1 checkpoint kinases.

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Smaill JB, Lee HH, Palmer BD, Thompson AM, Squire CJ, Baker EN, Booth RJ, Kraker A, Hook K, Denny WA

Synthesis and structure-activity relationships of soluble 8-substituted 4-(2-chlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-1,3(2H,6H)-diones as inhibitors of the Wee1 and Chk1 checkpoint kinases.

Bioorg Med Chem Lett. 2008 Feb 1;18(3):929-33. doi: 10.1016/j.bmcl.2007.12.046. Epub 2008 Jan 11.

PubMed ID

18191399 [ View in PubMed

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Abstract

Pyrrolo[3,4-c]carbazoles bearing solubilising basic side chains at the 8-position retain potent Wee1 and Chk1 inhibitory properties in isolated enzyme assays, and evidence of G2/M checkpoint abrogation in several cellular assays. Co-crystal structure studies confirm that the primary binding to the Wee1 enzyme is as described previously, with the C-8 side chains residing in an area of bulk tolerance.

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Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
9-HYDROXY-4-PHENYL-6H-PYRROLO[3,4-C]CARBAZOLE-1,3-DIONE	Wee1-like protein kinase	IC 50 (nM)	97	N/A	N/A	Details