Developing Programmable Genotoxin Targets Against Prostate Cancers

Life Sciences & Biotechnology Update, Feb, 2001

This (Massachusetts Institute of Technology) research has the objective to develop better chemotherapeutic drugs for the treatment of prostate cancers. Chemical synthetic methods are being used to create bifunctional compounds, consisting of ligands for the androgen receptor linked to a reactive alkylating group, that can produce covalent damage in cellular DNA. It is proposed that such damage would persist in tumor cells that express the androgen receptor (AR), because the DNA lesions would be masked by their association with the AR.

Initial work prepares chemically modified non-steroid and steroid derivatives that are tested for their affinity for the AR. The work then leads to the identification of structures that, when attached to a linker molecule, still retain good affinity for the AR. Subsequently, a number of bifunctional compounds are constructed and tested in biochemical assays and in prostate cancer cells in culture. A lead compound, containing an 11%-substituted steroid linked to an aniline mustard, is developed. This compound damages DNA and retains a good affinity for the AR, however, when added to prostate cancer cells in culture, its AR binding activity is lost. Experiments are being conducted to understand these results and to guide in the preparation of additional compounds.

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