Serving up anti-cancer cocktails: design, synthesis and evaluation of hybrid inhibitors

Scientists in the area of cancer drug development constantly find ways to target cancer’s Achilles heel. Bcr-Abl is a protein expressed in 95% of all Chronic Myelogenous Leukemia (a type of blood cancer) cases. It remains activated (i.e. switched ON) and instructs cancer cells to divide indefinitely. Bcr-Abl has remained an attractive target for therapy. Yet another attractive therapeutic target is Histone Deacetylase 1 (HDAC1) – a protein known to control cell survival via its ability to influence the turning on and turning off of certain genes.

Previous studies show that the drugs Dasatinib and MS-275 efficiently inhibit the cancer promoting activities of Bcr-Abl and HDAC1 respectively.  Clinical trials also suggest that these drugs, when used independently in separate studies, can be used to treat a variety of solid as well as blood-borne cancers. Bcr-Abl and HDAC1 are components of distinct cellular wiring systems, referred to as signalling pathways, which sustain cell survival and division. Single agent drugs, or drugs that stifle a single cancer-promoting pathway, weed out most cancer cells but also set the stage for drug-resistant cells. Reports suggest that both Dasatinib and MS-275 are associated with cancer drug resistance.

Multi-target inhibitors are a new and evolving class of cancer drugs that can simultaneously inhibit at least two signalling pathways. These compounds  have emerged as a potential solution in circumventing cancer drug resistance. Chen and colleagues at the Department of Organic Chemistry, School of Science, China Pharmaceutical University, China, designed and produced a series of hybrid drug molecules which combine the attributes of the HDAC inhibitor MS-275 with the Bcr-Abl inhibitor Dasatinib.

To determine the effect of the hybrid drugs on cancer cell survival, the research team tested the drug’s ability to halt the growth of three cell types exhibiting features of leukemia, kidney cancer and prostate cancer respectively. They found that all drugs in the series were toxic to cancer cells, with leukemia and kidney cancer cells showing the greatest degree of sensitivity to the hybrid drugs.

To better understand how the hybrid drugs interacted with the Bcr-Abl and HDAC1 active sites (i.e. the ON switch), the team relied on computer-generated three-dimensional models of the hybrid drugs, Bcr-Abl and HDAC1 proteins. Using a method similar to finding the right key for a lock, a computer program found that a hybrid compound termed 6a, which happened to be the most potent compound in the series, fit most snugly into both Bcr-Abl  and HDAC1 active sites. In theory, 6a would prevent both Bcr-Abl and HDAC1 from becoming activated (i.e they remain switched OFF).

On the basis of these observations, this study strengthens the paradigm that chemically melding two cancer drugs to form a novel single molecule may prove to be an effective clinical strategy for anticancer treatment. On a broader scale, this is one among many studies advocating for the use of multi-target agents in cancer treatment, highlighting an imminent upsurge in single molecule combination therapies.

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