Novel Histone Deacetylase Inhibitors
Abstract
The research goal is to demonstrate HDACl is a new chemotherapeutic target for human breast tumor cells and to identify new HDACl inhibitors on the basis of the structure of quinoline antimalarials. The drug screening strategy we used included S antimalarial compounds available through the NCI compound library or Sigma Chemical Company (quinoidine quinine, primaquine, chloroquine, hydroxychloroquine, halofantrine, mefloquine), 2 inactive quinolines as negative controls (quinoline, quinolinic acid), and trichostatin acid, a known HDACl inhibitor, as the positive control. The antimalarials caused differentiation of breast tumor cell lines and increased histone H4 acetylation. Only halofantrine, a non-quinoline antimalarial may directly inhibit HDACl enzyme activity. WE published that quinidine, a quinoline antimalarial, acts via a novel mechanism causing differentiation of breast tumor cells following a transient proteolytic degradation of the HDACl protein. Our screen has been extended to include 17 additional NCI compounds that possess a quinoline ring; their anticancer mechanisms are unknown, but we have preliminary evidence that several cause breast tumor differentiation. Analysis of these 27 compounds by molecular modeling is not yet complete.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2001
- Accession Number
- ADA396647
Entities
People
- Jeannie S. Strobl
Organizations
- West Virginia University