title: High-throughput assay for G2 checkpoint inhibitors and identification of the structurally novel compound isogranulatimide.
abstract: Treatment of cancer cells lacking p53 function with G2 checkpoint inhibitors sensitizes them to the toxic effects of DNA damage and has been proposed as a strategy for cancer therapy. However, few inhibitors are known, and they have been found serendipitously. We report the development of a G2 checkpoint inhibition assay that is suitable for high-throughput screening and its application to a screen of 1300 natural extracts. We present the isolation of a new G2 checkpoint inhibitor, the structurally novel compound isogranulatimide. In combination with gamma-irradiation, isogranulatimide selectively kills MCF-7 cells lacking p53 function.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, Canada. michel@otter.biochem.ubc.ca
authors.forename: M
authors.initials: M
authors.lastname: Roberge
authors.forename: R G
authors.initials: RG
authors.lastname: Berlinck
authors.forename: L
authors.initials: L
authors.lastname: Xu
authors.forename: H J
authors.initials: HJ
authors.lastname: Anderson
authors.forename: L Y
authors.initials: LY
authors.lastname: Lim
authors.forename: D
authors.initials: D
authors.lastname: Curman
authors.forename: C M
authors.initials: CM
authors.lastname: Stringer
authors.forename: S H
authors.initials: SH
authors.lastname: Friend
authors.forename: P
authors.initials: P
authors.lastname: Davies
authors.forename: I
authors.initials: I
authors.lastname: Vincent
authors.forename: S J
authors.initials: SJ
authors.lastname: Haggarty
authors.forename: M T
authors.initials: MT
authors.lastname: Kelly
authors.forename: R
authors.initials: R
authors.lastname: Britton
authors.forename: E
authors.initials: E
authors.lastname: Piers
authors.forename: R J
authors.initials: RJ
authors.lastname: Andersen
mesh_terms: D000230:Adenocarcinoma; D000818:Animals; D001943:Breast Neoplasms; D004260:DNA Repair; D016195:G2 Phase; D016158:Genes, p53; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D007211:Indoles / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D008175:Lung Neoplasms; D011838:Radiation-Sensitizing Agents / Q000302:isolation & purification*; D019311:Staurosporine / Q000737:chemistry; D013388:Succinimides / Q000737:chemistry; D014407:Tumor Cells, Cultured
chemical_list: D007093:Imidazoles; D007211:Indoles; D011838:Radiation-Sensitizing Agents; D013388:Succinimides; C116645:didemnimide A; C116644:isogranulatimide; D019311:Staurosporine