Tawnya C. McKee Molecular Targets Development Program, NCI Office: 301-846-1943 FAX: 301-846-6177 E-mail: mckee@ncifcrf.gov Job Title: Staff Scientist Ph.D. in Medicinal Chemistry from the University Utah

John A. Beutler Molecular Targets Development Program, NCI Office: 301-846-1942 FAX: 301-846-6177 E-mail: jb123w@nih.gov Job Title: Staff Scientist Ph.D. in Pharmacognosy from the Philadelphia College of Pharmacy and Science

Speaker: Tawnya C. McKee and John A. Beutler, Molecular Targets Development Program, Center for Cancer Research, NCI, Frederick, MD 21701

Topic: The Molecular Targets Development Program: Initiatives in High Throughput Screening and Higher Throughput Natural Products Research

Place: Building 549, Auditorium, NCI at Frederick, Frederick, MD

Time: Monday, April 26, 2004, at 10:00 AM

Abstract: The mission of the MTDP is the development of high throughput screens based on cancer related or cancer relevant molecular targets. These high throughput screens are developed in collaboration with PIs in the CCR and are designed to identify both bioprobes for these molecular targets, but also where possible, identify leads for chemotherapeutic agents. This program encompasses the historical strengths of the group including assay development and natural products-based drug discovery. One of the challenges in utilizing HTS is the enormous number of data points generated in a small amount of time. This is juxtaposed with a commonly stated problem of natural products research as being slow and expensive. We are also developing methods to increase throughput (and consequently speed) of the analysis of natural product extracts that are identified as HTS hits. This analysis primarily deals with dereplication methods which are utilized to identify the recurring nuisance compounds and to identify and prioritize the extracts which have the greatest probability of containing novel chemistry. One project where these principles have been put to use is in evaluating hits from a screen for inhibitors of HIV-1 RNase H activity. In addition to screening pure compound libraries, we have also screened over 82,000 natural product extracts, which yielded 1,161 confirmed hits. To rapidly evaluate these extracts, we have used a combination of biochemical assays, cellular assays, and rapid chemical separations. The use of a capillary electrophoresis-based biochemical assay, and arrayed solid-phase extraction methods have been particularly useful in facilitating evaluation of the extracts before fractionation.