DISCOVERY OF CDK INHIBITORS AS ANTITUMOR AGENTS

The discovery of inhibitors of cyclin/cyclin dependent kinase (cdk) complexes is proposed which may have an antiprolifertive/antitumor effect of cells. Because overexpression of various cyclins have differential oncogenic potential, inhibitors will be assayed against a panel of cyclin/cdks. The goal of Phase I is to discover a compound which inhibits one or more cyclin/cdk complexes with a 10-fold improvement in inhibition relative to the most potent inhibitors known. Structure-activity studies will be pursued to optimize inhibition within a given cyclin/cdk complex. In Phase I of this proposal, 6 to 10 analogues each of known cdk inhibitors (olomucine, and flavopiridol) will be synthesized in parallel and screened. We will also prepare peptide fragments relating to known protein phosphorylation sites and measure their inhibition potentials. Inhibition specificity will be examined by screening against all cyclin/cdk complexes, as well as, other commercially available serine/threonine or tyrosine kinases. Compounds exhibiting sub-micromolar inhibition or kinase specificity will be evaluated for their cytotoxic/cytostatic potential, and their effect on cell cycle distribution. More advanced biochemical evaluation and in vivo studies of the drug candidates will be included in Phase II of this program. $ = TOTAL AWARD AMTS & NOT LIMITED TO PORTION OF PROJECT RELATED TO SUBJECT OF SEARCH SUBPROJECT $ = TOTAL AWARD AMOUNT DIVIDED BY NUMBER OF SUBPROJECTS SOURCE: CRISP FORMAT F FY 97 LAST UPDATE 04-07-98 1QUERY 1536 ID SEARCH 06/01/98 PAGE 189 --PROJECT NUMBER......1 R43 CA75766-01 INVESTIGATOR NAME/ADDRESS FY 97 CHRISTOPHER, GAYLE K IRG/INTRAMURAL UNIT..ZRG7 DIVERSIFIED SCIENTIFIC INC AWARD AMOUNT......... $100,000 2800 MILAN COURT PERFORMING ORGANIZATION: DIVERSIFIED SCIENTIFIC, INC. TITLE HIGH RESOLUTION ROBOTIC TELEMAMMOGRAPHY SYSTEM ABSTRACT: Telemammography requires high spatial resolution, the transfer of large image files and rapid lossless transmission of images. Current teleradiology techniques fail to meet these requirements. A novel approach addressing these difficulties, involving robotic control of image acquisition, optical magnification and unique transmission strategies licensed from BellSouth Telecommunications, is proposed. Phase I goals include prototype development, software design and testing, objective characterization of the system and subjective system evaluation by a board certified radiologist. Following completion of Phase I, a Phase II application will be filed. Phase II will include optimization of system configuration, extensive testing and evaluation, both in-house and by consulting radiologists, culminating in clinical trials at a minimum of three sites. Following this we expect to file for FDA clearance of the device. This research should result in affordable, high resolution telemammography system that will provide better service to remote locations. With this system, even remote locations could have access to expertise and rapid diagnosis, affording women better care in a stressful time. This novel approach will have application to all of teleradiology, especially those specialties requiring a high spatial resolution.