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
| Autor: | Patrick Schweder, Mike Dragunow, Peter J. Choi, William A. Denny, Thomas I. H. Park, Elizabeth Cooper, Edward W. Mee, Richard L.M. Faull, Jiney Jose |
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| Rok vydání: | 2019 |
| Předmět: |
Cell Survival
medicine.drug_class Clinical Biochemistry Pharmaceutical Science Antineoplastic Agents 01 natural sciences Biochemistry Tyrosine-kinase inhibitor Structure-Activity Relationship Crizotinib Cell Line Tumor Drug Discovery medicine Humans Potency Cytotoxic T cell Anaplastic lymphoma kinase Molecular Biology IC50 Cell Proliferation Fluorescent Dyes Temozolomide Dose-Response Relationship Drug Molecular Structure Brain Neoplasms 010405 organic chemistry Chemistry Optical Imaging Organic Chemistry Carbocyanines Cytostatic Agents 0104 chemical sciences 010404 medicinal & biomolecular chemistry Cancer research Molecular Medicine Drug Screening Assays Antitumor Glioblastoma medicine.drug Conjugate |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 29:2617-2621 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2019.07.051 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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