AsianScientist (Mar. 19, 2015) – A genetic screen has identified a drug that is both damages cancer cell DNA and prevents in-built repair mechanisms. The results, published in EMBO Molecular Medicine, could lead to dual-targeting drugs that are more potent and have fewer side effects.
The majority of existing anticancer drugs attack single targets inside cancer cells. However, internal mechanisms for repairing drug-induced damage exist in cells and help cancer cells cope with the damage, significantly limiting the efficacy of existing drugs.
For example, nitrogen mustard drugs such as bendamustine cause DNA damage but have a limited potency because of intrinsic DNA repair pathways. A research group led by Professor Jiang Hai at the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences of Chinese Academy of Sciences collaborated with Crystal LLC, USA to screen a series of chemical derivatives of bendamustine. Among these, CY190602 displayed an unexpected 50 to 100 fold enhanced anticancer toxicity.
By using unique functional genetic screening system, CY190602 was found to harbor not only the traditional DNA damaging group, but also a novel histone deacetylase (HDAC) inhibitory activity in its side chain. Interestingly, after analyzing DNA repair genes, researchers found that several important DNA damage repair genes were all greatly suppressed after HDAC inhibition, reducing cellular DNA repair capacity. Therefore, they suggested that CY190602 not only attacks DNA, but also inhibits DNA repair in cancer cells, explaining its significantly enhanced anticancer efficacy.
In a series of mouse cancer models, CY190602 was found to be more effective than traditional anticancer drugs, while exhibiting less toxicity to normal cells such as hematopoietic stem cells. In a transplanted BCR-ABL driven acute lymphoblastic leukemia mouse model, CY190602 even rivaled the therapeutic effects of a BCR-ABL specific inhibitor.
The study of CY190602 as a prototype of DNA/HDAC dual-targeting drug demonstrated that it is possible to achieve higher potency against cancer cells by incorporating small enzyme inhibitory moiety into traditional DNA damaging drugs.
Importantly, the result showed that it is structurally compatible to incorporate small enzyme inhibitory chemical moieties into traditional DNA damage drugs, and such modifications can significantly enhance these drugs’ anticancer activity. Following the same rule, a number of novel drugs such as DNA/CDK1 dual-targeting drugs have been synthesized and exhibited high efficacy in preliminary studies.
Such kind of novel dual-targeting drugs may by itself improve cancer treatment, and their much-enhanced anticancer potency also offers new possibilities for antibody-coupled, tumor-targeting drug delivery research. This may provide several novel categories of anticancer drugs for clinical investigation.
The article can be found at: Liu et al. (2015) A DNA/HDAC Dual-Targeting Drug CY190602 with Significantly Enhanced Anticancer Potency.
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Source: Shanghai Institutes for Biological Sciences.
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