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.

Peter J Choi ¹, Elizabeth Cooper ², Patrick Schweder ³, Edward Mee ³, Clinton Turner ⁴, Richard Faull ⁵, William A Denny ¹, Mike Dragunow ⁶, Thomas I-H Park ⁶, Jiney Jose ⁷

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.

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