期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 29, 期 18, 页码 2617-2621出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2019.07.051
关键词
Glioblastoma multiforme; Temozolomide; Anaplastic lymphoma kinase; Crizotinib; Heptamethine cyanine dyes
资金
- Neurological Foundation of New Zealand
- Auckland Cancer Society Research Centre
- Health Research Council
- School of Medicine Foundation
- Hugh Green Foundation
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.
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