Development of a novel near-infrared fluorescent theranostic combretastain A-4 analogue, YK-5-252, to target triple negative breast cancer

Dual action prodrug, YK-5-252, reduces the toxicity of combretastatin A-4 (CA-4) and provides a theranostic imaging tool. [Display omitted] The treatment of triple negative breast cancer (TNBC) is a significant challenge to cancer research. The lack of hormone receptors limits the treatment options...

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Published in:	Bioorganic & medicinal chemistry Vol. 25; no. 7; pp. 2226 - 2233
Main Authors:	Kong, Yali, Smith, Jacqueline, Li, Kongwen, Cui, Jake, Han, John, Hou, Shujie, Brown, Milton L.
Format:	Journal Article
Language:	English
Published:	England Elsevier Ltd 01-04-2017
Subjects:	Benzopyrans - chemistry Benzopyrans - pharmacology Benzopyrans - therapeutic use Cell Line, Tumor Cell Proliferation - drug effects Flow Cytometry Humans Mass Spectrometry Proton Magnetic Resonance Spectroscopy Stilbenes - chemistry Stilbenes - pharmacology Stilbenes - therapeutic use Theranostic Nanomedicine Triple Negative Breast Neoplasms - drug therapy Triple Negative Breast Neoplasms - pathology Tubulin Modulators
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Summary:	Dual action prodrug, YK-5-252, reduces the toxicity of combretastatin A-4 (CA-4) and provides a theranostic imaging tool. [Display omitted] The treatment of triple negative breast cancer (TNBC) is a significant challenge to cancer research. The lack of hormone receptors limits the treatment options available to patients with this diagnosis, forcing them to endure prolonged radiation and chemotherapy. Anti-angiogenesis is a chemotherapeutic strategy that targets the vasculature of tumors. Combretastatin A-4 (CA-4) is a well-known vasculature-disrupting agent, which has been shown to effectively kill a variety of cancers through inhibition of tubulin polymerization. Due to its toxicity, small molecule analogues of CA-4 have been sought out. We have designed a novel dual action CA-4 prodrug, YK-5-252, which releases the drug through a disulfide bond cleavage mechanism and contains a near-infrared (NIR) fluorophore, which allows fluorescence monitoring of cleavage. This disulfide linkage causes CA-4 to become effective only when released by glutathione (GSH) reducing the toxicity of the drug while simultaneously releasing the NIR fluorophore. Therefore the prodrug, YK-5-252, represents a novel CA-4 analogue which has reduced toxicity and can be used for theranostics imaging.
ISSN:	0968-0896 1464-3391
DOI:	10.1016/j.bmc.2017.02.046