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Development and Operation of Drug Screening Models Relevant to Cancer A variety of drug screening models are either in operation or are under development that are relevant to discovering new drugs for treatment of cancer, AIDS, and opportunistic infections. These activities are conducted as dedicated efforts of the Operations and Technical Support Contract (SAIC-Frederick) at the National Cancer Institute - Frederick, or as subcontracts. Anticancer drug screening models include the established 60-tumor cell line screen and various high-throughput molecular targeted screens which are under development in the laboratory of Dr. Dominic Scudiero. Operation of the 60-cell screen has generated an information-rich, complex database for drug discovery research. Dr. David Covell, is pursuing a variety of approaches to exploiting this database for anticancer drug discovery. A variety of molecular-targeted high-throughput screening assays have been developed as a part of the activities required to establish the infrastructure for support of extramural and intramural drug discovery. These have been collaborative efforts with various scientists with expertise in specialized molecular target areas. Assay technologies have ranged from cell-free biophysical assays of macromolecular interaction, such as fluorescence polarization spectroscopy, through cell-based assays using luciferase reporter constructs. The HIF-1 screen of Giovanni Melillo serves as an example of the latter assay type.
Credentials Dr. Shoemaker obtained his Ph.D. in human genetics from the Graduate School of Public Health of the University of Pittsburgh in 1975. Following postdoctoral experience at the Armed Forces Institute of Pathology at the Walter Reed Army Medical Center he joined the Department of Pathology of the Children's Hospital Medical Center of Akron. His research on pediatric tumors led to an interest in the genetics of drug resistance and subsequently to an interest in new drug discovery and development. Since joining the National Cancer Institute in 1981, Dr. Shoemaker has held a variety of positions in the extramural Developmental Therapeutics Program dealing with development and implementation of novel drug screening projects relevant to cancer and AIDS. From 1990 to 1999 Dr. Shoemaker was a Senior Investigator and Section Head in the Laboratory of Drug Discovery Research and Development, achieving intramural tenure in 1992. In 1999, Dr. Shoemaker was appointed Chief of the Antiviral Evaluations Branch, a position which evolved into his present position as Chief of the Screening Technologies Branch. His research interests include identification and exploitation of molecular targets for drug discovery, development of clinically relevant methods for target monitoring, and natural products-based drug discovery. Recent Publications NCBI PubMed listing of publications by Robert Shoemaker. Dorjsuren, Dorjbal, Burnette, Angela , Gray, Glenn N., Chen Xulin, Zhu, Weimin, Roberts, Paula E., Currens, Michael J., Shoemaker, Robert H., Ricciardi, Robert P. and Sei, Shizuko. Chemical Library Screen for Novel Inhibitors of Kaposi’s Sarcoma-associated Herpesvirus Processive DNA Synthesis. Antiviral Research 69:9-23, 2006. Fisher, R.J., Fivash, M.J., Stephen, A.G., Medaglia, M.V., Smith, L.R., Worthy, K.M., Simpson, T.J., Shoemaker, R. McNitt, K.L., Johnson, D.G., Hixton, K.V., Gorelick, R. J., Henderson, L.E. and Rein, A. Complex interactions with HIV-a nucleocapsid protein with oligonucleotides. Nucleic Acid Research 34:472-484, 2006. Jensen, L.H., Tougaard, A.V., Sokilde, B., Grauslund, M., Carstensen, E.V., Nielsen, H.D., Scudiero, D., Jensen, P.B., Shoemaker, R.H. and Sehested, M. Substituted purine analogs define a novel structural class of catalytic topoisomerase II inhibitors. Cancer Research 65:7470-7477, 2005. Calvani, Maura, Rapisarda, Annamaria, Uranchimeg, Badarch, Shoemaker, Robert H. and Melillo, Giovanni. Hypoxic induction of a HIF-1-dependent bFGF autocrine loop drives angiogenesis in human endothelial cells. Blood First Edition Paper, prepublished online November 22, 2005; DOI 10.1182/blood-2005-09-3541. Dayam R., Sanchez, T., Clement, O., Shoemaker, R., Sei, S. and Neamati, N. Beta-Diketo acid pharmacophore hypothesis. 1. Discovery of a novel class of HIV-1 integrase inhibitors. Journal of Medicinal Chemistry 48:111-20, 2005. Yang, Quan-en, Stephen, Andrew G., Adelsberger, Joseph W., Roberts, Paula E., Zhu, Weimin, Currens, Michael J., Feng, Yaxiong, Crise, Bruce, Gorelick, Robert, Rein, Alan R., Fisher, Robert J., Shoemaker, Robert H. and Sei, Shizuko. Discovery of small-molecule HIV-1 entry inhibitors that target the gp-120 binding domain of cd4. Journal of Virology 79:6122-6133, 2005. Rishi, Vikas, Potter, Timothy, Laudeman, Julie, Reinhart, Russel, Silvers, Thomas, Selby, Michael, Stevenson, Timothy, Krosky, Paula, Stevens, Andy, Acharya, Asha, Moll, John, Oh, Won-Jun, Scudiero, Dominic, Shoemaker, Robert H. and Vinson, Chris. A high-throughput fluorescence –anisotropy screen that identifies small molecule inhibitors of the DNA binding of B_ZIP transcription factors. Analytical Biochemistry 340:259-71, 2005. Klausmeyer, P., McCloud, T.G., Tuicker, K.D., Cardellina, J.H. and Shoemaker, R.H. Aspirochorine class compounds from aspirgillus flavus inhibit resistant fungi. Journal of Natural Products 68:1300-1302, 2005. Kong, Dehe, Park, Eun Jung, Stephen, Andy, Calvani, Maura, Cardellina, John, Monks, Anne, Fisher, Robert, Shoemaker, Robert H., and Mellilo, Giovanni. Echinomycin, a small molecule inhibitor of HIF-1 DNA binding activity. Cancer Research 65:9047-9055, 2005. Zhu, Weimin, Burnette, Angela, Dorjsuren, Dorjbal, Roberts, Paula E., Huleihel, Mahmoud, Shoemaker, Robert H., Marquez, Victor, Agbaria, Riad and Sei, Shizuko. Potent antiviral activity of North-methanocarbathymidine against Kaposi’s Sarcoma-associated herpesvirus. Antimicrobial Agents and Chemotherapy 49:4965-73, 2005. Meragelman, Tamara L., Tucker, Kenneth D., McCloud, Thomas G., Cardellina II, John H., Shoemaker, Robert H.. Antifungal flavonoids from Hildegardia barteri. Journal of Natural Products 68:1790-1792, 2005.Shoemaker, Robert H., Scudiero, Dominic A., Melillo, Giovanni, Currens, Michael J., Monks, Anne P., Rabow, Alfred A., Covell, David G. and Sausville, Edward A. Application of High-Throughput, Molecular-Targeted Screening to Anticancer Drug Discovery. Current Topics in Medicinal Chemistry 2:229-246, 2002. Pdf. |
