Many academic researchers have excellent expertise in discovering proteins, ehzymes or genes that may be involved in cancer development or response to therapy. However, exploitation of these systems as targets for therapeutic drug development requires interests, experience and resources beyond those present in a typical research laboratory environment. This results in a lost opportunity for the researcher to demonstrate a role of the target in the disease state, as well as the loss of an opportunity to discover compounds with therapeutic potential. In a pharmaceutical company, such discovery would-most likely take place within a dedicated screening/chemistry division. This proposal seeks funding to establish a similar, albeit clearly more limited, core facility at Penn State University. The goal of this Drug Discovery Core Facility (DDCF) is to enable the development of faculty-identified proteins and/or genes as targets for anticancer drugs. This will proceed through the following interacting steps. The DDCF will closely collaborate with the Faculty Researcher to develop assays for inhibitors or activators of their protein of interest. The DDCF will maintain a collection of compounds to be tested in these assays, conduct the actual screening process and analyze data by molecular modeling for Quantitative Structure-Activity Relationships (QSARs). At this point, the Project Leader will have lead compounds and defined families of compounds upon which further study can be focused. For example, the lead compounds will provide useful new tools .for the pharmacological manipulation of the target and evaluation of biological consequences. Additionally, the QSAR information could then be used to direct the synthesis of new optimized compounds and/or the purchase of commercially available compounds. The recent availability of commercial screening libraries, equipment for medium-throughput screening, and software for ligand-based QSAR development has enabled this approach to drug discovery in an academic environment. The feasibility of this process has been validated by the experience of the Principal Investigator in developing novel antagonists of drug transport proteins. Establishment of this DDCF will provide an important bridge between basic and applied research, and so will enhance the research environment and advance cancer research.
| Lee, Brian D; Li, Zhanjiang; French, Kevin J et al. (2004) Synthesis and evaluation of dihydropyrroloquinolines that selectively antagonize P-glycoprotein. J Med Chem 47:1413-22 |
