@article {896,
	title = {Inhibition of Chk1 by the G(2) DNA damage checkpoint inhibitor isogranulatimide},
	journal = {Molecular Cancer Therapeutics},
	volume = {3},
	number = {10},
	year = {2004},
	note = {ISI Document Delivery No.: 862KBTimes Cited: 40Cited Reference Count: 40},
	month = {Oct},
	pages = {1221-1227},
	type = {Article},
	abstract = {Inhibitors of the G(2) DNA damage checkpoint can selectively sensitize cancer cells with mutated p53 to killing by DNA-damaging agents. Isogranulatimide is a G2 checkpoint inhibitor containing a unique indole/maleimide/ imidazole skeleton identified in a phenotypic cell-based screen; however, the mechanism of action of isogranulatimide is unknown. Using natural and synthetic isogranulatimide analogues, we show that the imide nitrogen and a basic nitrogen at position 14 or 15 in the imidazole ring are important for checkpoint inhibition. Isogranulatimide shows structural resemblance to the aglycon of UCN-01, a potent bisindolemaleimide inhibitor of protein kinase Cbeta (IC50, 0.001 mumol/L) and of the checkpoint kinase Chk1 (IC50, 0.007 mumol/L). In vitro kinase assays show that isogranulatimide inhibits Chk1 (IC50, 0.1 mumol/L) but not protein kinase Cbeta. Of 13 additional protein kinases tested, isogranulatimide significantly inhibits only glycogen synthase kinase-3beta (IC50, 0.5 mumol/L). We determined the crystal structure of the Chk1 catalytic domain complexed with isogranulatimicle. Like UCN-01, isogranulatimide binds in the ATP-binding pocket of Chk1 and hydrogen bonds with the backbone carbonyl oxygen of Glu(85) and the amide nitrogen Of Cys(87). Unlike UCN-01, the basic N15 of isogranulatimide interacts with Glu(17), causing a conformation change in the kinase glycine-rich loop that may contribute importantly to inhibition. The mechanism by which isogranulatimide inhibits Chk1 and its favorable kinase selectivity profile make it a promising candidate for modulating checkpoint responses in tumors for therapeutic benefit.},
	keywords = {7-HYDROXYSTAUROSPORINE UCN-01, ACTIVATION, CANCER, CELL-CYCLE, DEPENDENT PROTEIN-KINASE, IDENTIFICATION, MECHANISMS, PHOSPHORYLATION, SPECIFICITY, SUBSTRATE},
	isbn = {1535-7163},
	url = {<Go to ISI>://000224488400006},
	author = {Jiang, X. X. and Zhao, B. G. and Britton, R. and Lim, L. Y. and Leong, D. and Sanghera, J. S. and Zhou, B. B. S. and Piers, E. and Andersen, R. J. and Roberge, M.}
}
@article {760,
	title = {Trisphaerolide A, a novel polyketide from the Dominican sponge Erylus trisphaerus},
	journal = {Journal of Natural Products},
	volume = {66},
	number = {4},
	year = {2003},
	note = {ISI Document Delivery No.: 673CVTimes Cited: 4Cited Reference Count: 14},
	month = {Apr},
	pages = {561-563},
	type = {Article},
	abstract = {The structure of trisphaerolide A (1), a mildly cytotoxic metabolite isolated from extracts of the marine sponge Erylus trisphaerus collected in Dominica, has been elucidated by detailed analysis of spectroscopic data. Trisphaerolide A (1) has a putative polyketide biogenesis, incorporating a rare variant on the standard pathway, which involves the addition of methyl branches arising from C-2 carbons of acetate units to chain carbons that arise from C-1 of acetate units.},
	keywords = {biosynthesis, CELL-CYCLE, DNA-DAMAGE CHECKPOINT, INHIBITION, ISOGRANULATIMIDE},
	isbn = {0163-3864},
	url = {<Go to ISI>://000182562800025},
	author = {van Altena, I. and Van Soest, R. and Roberge, M. and Andersen, R. J.}
}
