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CY190602, a novel DNA/HDAC dual-targeting drug with enhanced anti-cancer potency

 

Genotoxic drugs are effective chemotherapies that induce death to cancer cells by attacking cellular DNA. One double-strand break (DSB) resulting from such attacks is sufficient to induce cell death. However, some less potent lethality induced by anti-cancer drugs can be attenuated by cellular DNA repair machinery, which may finally lead to treatment failure. Previous studies have reported important roles of histone deacetylases (HDACs) in DNA repair, that may interfere with the efficiency of genotoxic drugs. Liu et al. demonstrated a novel bendamustine-derived drug, CY190602, enhanced anticancer potency. The article was published in EMBO Molecular Medicine.

 

Bendamustine, a nitrogen mustard, is recently approved for treating many cancers, including chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), follicular lymphoma (FL), and mantle-cell lymphoma (MCL). However, the poor drug potency hinders efficacy of bendamustine. Researchers reported the development and characterization of bendamustine -derived CY190602, and proved its enhanced potency is attributed to its ability to inhibit HDACs. By using this novel DNA/HDAC dual-targeting drug, researchers found HDAC activities are essential for the expression of several genes related to DNA synthesis and repair, including TYMS, Tip60, CBP, EP300, and MSL1. The enhanced in vitro and in vivo anti-cancer activity of CY190602 indicates systematic development of DNA/HDAC dual-targeting drugs may provide new strategies for optimizing cancer therapy.

 

Reference:
EMBO Mol Med. 2015 Mar 9. pii: e201404580.

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Cat.No. Product Name Information
S1212 Bendamustine HCl Bendamustine HCl is a DNA-damaging agent with IC50 of 50 μM in cell-free assay.
S1047 Vorinostat (SAHA) Vorinostat (SAHA) is an HDAC inhibitor with IC50 of ~10 nM in a cell-free assay. Vorinostat abrogates productive HPV-18 DNA amplification.
S1491 Fludarabine Fludarabine is a STAT1 activation inhibitor which causes a specific depletion of STAT1 protein (and mRNA) but not of other STATs. Also a DNA synthesis inhibitor in vascular smooth muscle cells. Fludarabine induces apoptosis.

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HDAC STAT DNA/RNA Synthesis Autophagy