Design, synthesis and biological activity of novel molecules designed to target PARP and DNA

• Published in: Bioorganic & medicinal chemistry letters Vol. 27; no. 3; pp. 688 - 694
• Main Authors: Goodfellow, Elliot, Senhaji Mouhri, Zhor, Williams, Christopher, Jean-Claude, Bertrand J.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.02.2017; Elsevier
• Subjects: Animals; Binding Sites; Bis-targeting; BRCA mutation; BRCA2 Protein - deficiency; BRCA2 Protein - genetics; Chemistry; Chemistry, Medicinal; Chemistry, Organic; CHO Cells; Cricetinae; Cricetulus; DNA - chemistry; DNA - metabolism; DNA damage; DNA Damage - drug effects; Drug Design; Enzyme Activation - drug effects; Life Sciences & Biomedicine; Molecular Docking Simulation; PARP inhibitors; Pharmacology & Pharmacy; Physical Sciences; Poly(ADP-ribose) Polymerase Inhibitors - chemical synthesis; Poly(ADP-ribose) Polymerase Inhibitors - chemistry; Poly(ADP-ribose) Polymerase Inhibitors - pharmacology; Poly(ADP-ribose) Polymerases - chemistry; Poly(ADP-ribose) Polymerases - metabolism; Protein Structure, Tertiary; Science & Technology; Synthetic lethality; Synthetic lethality; Bis-targeting; PARP inhibitors; DNA damage; BRCA mutation; PATHWAYS; PROTECTION; POLYMERASE; BREAST; MUSTARD; GROWTH-FACTOR RECEPTOR; REPAIR; LETHALITY; INHIBITOR; COMBI-MOLECULES
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2016.09.054

[Display omitted] 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.