title: Comparative chemogenomics to examine the mechanism of action of dna-targeted platinum-acridine anticancer agents.
abstract: Platinum-based drugs have been used to successfully treat diverse cancers for several decades. Cisplatin, the original compound of this class, cross-links DNA, resulting in cell cycle arrest and cell death via apoptosis. Cisplatin is effective against several tumor types, yet it exhibits toxic side effects and tumors often develop resistance. To mitigate these liabilities while maintaining potency, we generated a library of non-classical platinum-acridine hybrid agents and assessed their mechanisms of action using a validated genome-wide screening approach in Saccharomyces cerevisiae and in the distantly related yeast Schizosaccharomyces pombe. Chemogenomic profiles from both S. cerevisiae and S. pombe demonstrate that several of the platinum-acridines damage DNA differently than cisplatin based on their requirement for distinct modules of DNA repair.
authors.affiliation: Department of Molecular Genetics and the Donnelly Centre, University of Toronto, Toronto, ON, M5S3E1 Canada.
authors.forename: Kahlin
authors.initials: K
authors.lastname: Cheung-Ong
authors.forename: Kyung Tae
authors.initials: KT
authors.lastname: Song
authors.forename: Zhidong
authors.initials: Z
authors.lastname: Ma
authors.forename: Daniel
authors.initials: D
authors.lastname: Shabtai
authors.forename: Anna Y
authors.initials: AY
authors.lastname: Lee
authors.forename: David
authors.initials: D
authors.lastname: Gallo
authors.forename: Lawrence E
authors.initials: LE
authors.lastname: Heisler
authors.forename: Grant W
authors.initials: GW
authors.lastname: Brown
authors.forename: Ulrich
authors.initials: U
authors.lastname: Bierbach
authors.forename: Guri
authors.initials: G
authors.lastname: Giaever
authors.forename: Corey
authors.initials: C
authors.lastname: Nislow
mesh_terms: D000166:Acridines / Q000737:chemistry* / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D002945:Cisplatin / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects*; D004271:DNA, Fungal / Q000235:genetics; D023281:Genomics; D009944:Organoplatinum Compounds / Q000737:chemistry* / Q000494:pharmacology*; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics; D012568:Schizosaccharomyces / Q000187:drug effects / Q000235:genetics
chemical_list: D000166:Acridines; D000970:Antineoplastic Agents; D004271:DNA, Fungal; D009944:Organoplatinum Compounds; D002945:Cisplatin