PARP inhibitor cyanine dye conjugate with enhanced cytotoxic and antiproliferative activity in patient derived glioblastoma cell lines

Peter J Choi; Elizabeth Cooper; Patrick Schweder; Edward Mee; Clinton Turner; Richard Faull; William A Denny; Mike Dragunow; Thomas I-H Park; Jiney Jose

doi:10.1016/j.bmcl.2020.127252

PARP inhibitor cyanine dye conjugate with enhanced cytotoxic and antiproliferative activity in patient derived glioblastoma cell lines

Bioorg Med Chem Lett. 2020 Jul 15;30(14):127252. doi: 10.1016/j.bmcl.2020.127252. Epub 2020 May 8.

Authors

Affiliations

¹ Auckland Cancer Society Research Centre, School of Medical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
² Auckland Cancer Society Research Centre, School of Medical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; Department of Pharmacology & The Centre for Brain Research, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; Neurosurgical Research Unit, The Centre for Brain Research, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
³ Neurosurgical Research Unit, The Centre for Brain Research, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; Department of Neurosurgery, Auckland City Hospital, Private Bag 92024, Auckland 1142, New Zealand.
⁴ Department of Anatomical Pathology, LabPlus, Auckland City Hospital, 2 Park Road, Auckland, New Zealand.
⁵ Neurosurgical Research Unit, The Centre for Brain Research, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
⁶ Department of Pharmacology & The Centre for Brain Research, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; Neurosurgical Research Unit, The Centre for Brain Research, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
⁷ Auckland Cancer Society Research Centre, School of Medical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. Electronic address: j.jose@auckland.ac.nz.

PMID: 32527552
DOI: 10.1016/j.bmcl.2020.127252

Abstract

We describe the synthesis and in vitro activity of drug-dye conjugate 1, which is a combination of the PARP inhibitor rucaparib and heptamethine cyanine dye IR-786. The drug-dye conjugate 1 was evaluated in three different patient-derived glioblastoma cell lines and showed strong cytotoxic activity with nanomolar potency (EC₅₀: 128 nM), which was a 780 fold improvement over rucaparib itself. We also observe a synergistic effect of 1 with temozolomide (TMZ), the standard drug for treatment for glioblastoma even though these cell lines were resistant to TMZ treatment. We envisage such conjugates to be worth exploring for their utility in the treatment of various brain cancers.

Keywords: Glioblastoma; Heptamethine cyanine dyes; PARP inhibitors; Rucaparib; Temozolomide.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Brain Neoplasms / drug therapy*
Brain Neoplasms / metabolism
Brain Neoplasms / pathology
Carbocyanines / chemistry
Carbocyanines / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Glioblastoma / drug therapy*
Glioblastoma / metabolism
Glioblastoma / pathology
Humans
Indoles / chemistry
Indoles / pharmacology*
Molecular Structure
Poly(ADP-ribose) Polymerase Inhibitors / chemical synthesis
Poly(ADP-ribose) Polymerase Inhibitors / chemistry
Poly(ADP-ribose) Polymerase Inhibitors / pharmacology*
Poly(ADP-ribose) Polymerases / metabolism*
Structure-Activity Relationship

Substances

Antineoplastic Agents
Carbocyanines
IR-786
Indoles
Poly(ADP-ribose) Polymerase Inhibitors
rucaparib
Poly(ADP-ribose) Polymerases