title: Design, synthesis and biological activity of novel molecules designed to target PARP and DNA.
abstract: In order to enhance the cytotoxic potential of poly(ADP-ribose) polymerase (PARP) inhibitors in BRCA1 or 2 deficient tumours, we designed a series of molecules containing a 1,2,3-triazene moiety tethered to a PARP targeting scaffold. A cell-based selectivity assay involving a BRCA2-deficient Chinese hamster cell line and its corresponding BRCA2 wild type transfectant, was used to predict the PARP targeting potential of the latter agents. The results showed that adding a DNA damaging function to the PARP inhibitors decreased but did not abrogate the selective targeting of the BRCA2-deficient cells. The DNA damaging moiety augmented the potency in BRCA2 deficient cells by 2-20 fold. The most selective dual PARP-DNA targeting agent 14b was found to possess dual DNA and PARP targeting properties.
authors.affiliation: Cancer Drug Research Laboratory, Department of Medicine, Division of Medical Oncology, McGill University Health Center/Glen Hospital, 1001 Decarie Blvd, Montreal H4A 3J1, Quebec, Canada.
authors.forename: Elliot
authors.initials: E
authors.lastname: Goodfellow
authors.affiliation: Cancer Drug Research Laboratory, Department of Medicine, Division of Medical Oncology, McGill University Health Center/Glen Hospital, 1001 Decarie Blvd, Montreal H4A 3J1, Quebec, Canada.
authors.forename: Zhor
authors.initials: Z
authors.lastname: Senhaji Mouhri
authors.affiliation: Chemical Computing Group Inc., 1010 Sherbrooke Street West, Suite 910, Montreal H3A 2R7, Quebec, Canada.
authors.forename: Christopher
authors.initials: C
authors.lastname: Williams
authors.affiliation: Cancer Drug Research Laboratory, Department of Medicine, Division of Medical Oncology, McGill University Health Center/Glen Hospital, 1001 Decarie Blvd, Montreal H4A 3J1, Quebec, Canada. Electronic address: bertrandj.jean-claude@mcgill.ca.
authors.forename: Bertrand J
authors.initials: BJ
authors.lastname: Jean-Claude
mesh_terms: D000818:Animals; D024682:BRCA2 Protein / Q000172:deficiency / Q000235:genetics; D001665:Binding Sites; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D004249:DNA Damage / Q000187:drug effects; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D062105:Molecular Docking Simulation; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000737:chemistry / Q000378:metabolism*; D017434:Protein Structure, Tertiary
chemical_list: D024682:BRCA2 Protein; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D004247:DNA; D011065:Poly(ADP-ribose) Polymerases
keywords: BRCA mutation; Bis-targeting; DNA damage; PARP inhibitors; Synthetic lethality