The synthesis of a novel Crizotinib heptamethine cyanine dye conjugate that potentiates the cytostatic and cytotoxic effects of Crizotinib in patient-derived glioblastoma cell lines

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

doi:10.1016/j.bmcl.2019.07.051

The synthesis of a novel Crizotinib heptamethine cyanine dye conjugate that potentiates the cytostatic and cytotoxic effects of Crizotinib in patient-derived glioblastoma cell lines

Bioorg Med Chem Lett. 2019 Sep 15;29(18):2617-2621. doi: 10.1016/j.bmcl.2019.07.051. Epub 2019 Jul 29.

Authors

Peter J Choi¹, Elizabeth Cooper², Patrick Schweder³, Edward Mee³, Richard Faull⁴, William A Denny¹, Mike Dragunow⁵, Thomas I-H Park⁵, Jiney Jose¹

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 Neurosurgical Research Unit, The Centre for Brain Research, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
⁵ 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.

PMID: 31378572
DOI: 10.1016/j.bmcl.2019.07.051

Abstract

We describe the synthesis of drug-dye conjugate 1 between anaplastic lymphoma kinase inhibitor Crizotinib and heptamethine cyanine dye IR-786. The drug-dye conjugate 1 was evaluated in three different patient-derived glioblastoma cell lines and showed potent cytotoxic activity with nanomolar potency (EC₅₀: 50.9 nM). We also demonstrate evidence for antiproliferative activity of 1 with single digit nanomolar potency (IC₅₀: 4.7 nM). Furthermore, the cytotoxic effects conveyed a dramatic, 110-fold improvement over Crizotinib. This improvement was even more pronounced (492-fold) when 1 was combined with Temozolomide, the standard drug for treatment for glioblastoma. This work lays the foundation for future exploration of similar tyrosine kinase inhibitor drug-dye conjugates for the treatment of glioblastoma.

Keywords: Anaplastic lymphoma kinase; Crizotinib; Glioblastoma multiforme; Heptamethine cyanine dyes; Temozolomide.

Publication types

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

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Brain Neoplasms / diagnostic imaging
Brain Neoplasms / drug therapy*
Brain Neoplasms / metabolism
Carbocyanines / chemistry
Carbocyanines / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Crizotinib / chemistry
Crizotinib / pharmacology*
Cytostatic Agents / chemical synthesis
Cytostatic Agents / chemistry
Cytostatic Agents / pharmacology*
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Fluorescent Dyes / chemical synthesis
Fluorescent Dyes / chemistry
Fluorescent Dyes / pharmacology*
Glioblastoma / diagnostic imaging
Glioblastoma / drug therapy*
Glioblastoma / metabolism
Humans
Molecular Structure
Optical Imaging
Structure-Activity Relationship

Substances

Antineoplastic Agents
Carbocyanines
Cytostatic Agents
Fluorescent Dyes
Crizotinib