Anti-mitotic Eg5 inhibitors for the treatment of cancer and inflammatory disease
Small molecule compounds, dihydropyrancarboxamides
Molecules targeting mitosis and microtubule stability are important for the treatment of cancer. Unfortunately, the mechanism of action of these agents can cause undesirable toxicities For example, antimitotic agents such as taxol, epothilone, and vinca alkaloids produce toxicity in peripheral neurons, leading to chronic neuropathy. In addition, many of these agents are subject to acquired resistance. As such, researchers often look to new targets for development of antimitotic agents. One such target is the microtubule associated kinesin Eg5. Eg5 is a member of the kinesin-5 family and plays an important role in the early stages of mitosis. Studies have shown that inhibition of Eg5 leads to cell cycle arrest during mitosis and causes cells to develop a monopolar spindle. It is believed that because Eg5 is not expressed in postmitotic neurons and likely to act only in dividing cells, its inhibition might provide better specificity than microtubule inhibitors in the treatment of human malignancies.
These dihydropyrancarboxamide compounds are useful in the treatment of cell proliferative disorders such as cancer and immune conditions. The inventive compounds may also be utilized in assays identifying compounds having a biological activity of interest, for example, target enzymes, DNA synthesis, toxicity evaluation or bioavailability assessment.
Innovations and Advantages
The invention is a novel class of small molecule compounds, dihydropyrancarboxamides, which inhibit the mitotic kinesin Eg5. The dihydropyrancarboxamide compounds were identified in a high-throughput screen to identify novel anti-mitotic compounds. The compounds have a wide range of biological properties, such as inducing mitotic arrest phenotype and inhibiting ATP hydrolysis in vitro similar to the effect of other reported Eg5 inhibitors. Included in the invention are also novel methods for synthesis of these compounds.
The compounds are roughly 10 times more potent than previous Eg5 inhibitors in vitro with less toxicity and more solubility in water. Any available techniques can be used to make or prepare dihydropyrancarboxamides. For example, combinatorial techniques, parallel synthesis and/or solid phase synthetic methods may be used as well as any variety of solution phase synthetic methods.
Intellectual Property Status: US Patent 7,186,709
Asymmetric Catalysis in Diversity-Oriented Organic Synthesis: Enantioselective Synthesis of 4320 Encoded and Spatially Segregated Dihydropyrancarboxamides. 2001. Angew. Chem. Int. Ed., 40(18): 3417-3421.
Mitchison, Timothy J.
Schreiber, Stuart L.
Stavenger, Robert A.
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Vivian Berlin, Director of Business Development
Reference Harvard Case #2060