As director of the pharmacology core component of an NCI-funded program project grant in cancer, my research is focused on developing novel chemical leads as viable therapeutics in vivo. This includes exploring issues related to compound formulation, compound metabolic stability, in vivo pharmacokinetics and toxicology, as well as development of animal models suitable to the targeted signaling pathway. We have provided preclinical pharmacology support for a variety of novel compound families many with potential anti-cancer activity, but also including antimicrobials and agents targeted at the central nervous system. The numbers and types of projects reaching our laboratory has been increasing rapidly in the past year. These include analysis of compounds from natural products-based chemical syntheses as well as rational target-based chemical design. In addition, a number of high throughput screens have identified compounds that are ready for testing in animals. The rising interest in the identification of small molecules for use as probes or therapeutic leads brings preclinical pharmacology to the interest of academic scientists, as increasingly research goals require studies in animals. To evaluate such experiments, one must know whether the compound is reaching the target of interest in sufficient quantitites to be efficacious and with kinetics appropriate to the chosen schedule and route of administration. I am most interested in asking whether anticancer drugs with more targeted molecular activity show less whole animal toxicity than conventional chemotherapeutics.
RESEARCH INTERESTS
pharmacokinetics
toxicology
apoptosis and cell division
small molecule therapeutics
RECENT PUBLICATIONS
A. Zhou, S. Scoggin, R. B. Gaynor, and N. S. Williams, "Identification of NF-kB-regulated genes induced by TNFa using expression profiling and RNA interference" Oncogene, 22:2054-2064, 2003
Williams, N. S., R. B. Gaynor, S. Scoggin, U. Verma, T. Gokaslan, C. Simmang, J. Fleming, D. Tavana, E. Frenkel, and C. Becerra, "Identification and validation of genes involved in the pathogenesis of colorectal cancer utilizing microarrays and RNA interference" Clinical Cancer Research, 9:931-946, 2003
Xin, J., Williams, N., De Brabander, J, "Synthesis of psymberin analogs: probing a functional correlation with the pederin/mycalamide family of natural products" Organic Letters, 9:227-230, 2007
Williams, N.S., Burgett, A.W.G., Atkins, A.S., Wang, X., Harran, P.G., and McKnight, S.L., "Therapeutic anti-cancer efficacy of a synthetic diazonamide analog in the absence of overt toxicity" Proc. Natl. Acad. Sci. USA, 104:2074-2079, 2007
SIGNIFICANT PUBLICATIONS
Williams, N.S., R.B. Gaynor, S. Scoggin, U. Verma, T. Gokaslan, C. Williams, N.S., R.B. Gaynor, S. Scoggin, U. Verma, T. Gokaslan, C. Simmang, J. Fleming, D. Tavana, E. Frenkel, and C. Becerra., "Identification and validation of genes involved in the pathogenesis of colorectal cancer utilizing cDNA microarrays and RNA interference." Clinical Cancer Research, 9:931-946, 2003
Williams, N. S., J. Klem. I. J. Puzanov, P. V. Sivakumar, J. D. Schatzle, M. Bennett, and V. Kumar, "Natural killer cell differentiation: insights from knockout and transgenic mouse models and in vitro systems." Immunological Reviews, 165:47-61, 1998
Williams, N. S., T. A. Moore, J. D. Schatzle, I. J. Puzanov, P. V. Sivakumar, A. Zlotnik, M. Bennett, and V. Kumar, "Generation of lytic NK1.1+, Ly-49- cells from multipotential murine bone marrow progenitors in a stroma-free culture: definition of cytokine requirements and developmental intermediates." Journal of Experimental Medicine, 186:1609-1614, 1997
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