Programmable Genotoxins Targeted Against Prostate Cancers
Abstract
The purpose of our research is to develop better chemotherapeutic drugs for the treatment of prostate cancers. We have used chemical synthetic methods to create bifunctional compounds consisting of a 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 prepared chemically modified non-steroid and steroid derivatives that were tested for their affinity for the AR. This work led to the identification of structures that when attached to a linker molecule still retained good affinity for the AR. Subsequently, a number of bifunctional compounds were constructed and tested in biochemical assays and in prostate cancer cells in culture. We have identified a lead compound containing an 11 %-substituted steroid linked to an aniline mustard. This compound damaged DNA and retained good affinity for the AR. We discovered, however, that when added to prostate cancer cells in culture its AR binding activity is lost. We are conducting experiments of understand these results and guide us in the preparation of additional compounds.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 1999
- Accession Number
- ADA380921
Entities
People
- John Essigmann
Organizations
- Massachusetts Institute of Technology