CANCER DRUG DISCOVERY: CELL CYCLE CONTROL TARGETS

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The overall goal of this program project application is to discover anti- cancer drugs based on disrupting aberrant cell cycle transduction pathways. Combinatorial chemistry and phage display peptide libraries will be used to create structural diversity, and biochemical and cell-based assays will be devoted to target molecular events critical to neoplastic transformation. The central theme of this proposal will focus on three cycle control targets: receptor tyrosine kinases (RTK), signal transducers and activators of transcription (STAT) and cyclin-dependent kinases (CDK). Our multi-disciplinary approach to accomplish the overall goal consists of four distinct but complementary projects. Project 1 will use structural and molecular information and peptide hits from phage display peptide libraries to synthesize combinatorial libraries that will create a large number of compounds with the potential of disrupting RTK and their ligands, STAT and CDK oncogenic signaling. Project 2 will use peptide hits as well as combinatorial libraries synthesized by Project 1 to disrupt growth factor binding to their RTK, receptor tyrosine auto- phosphorylation and RTK oncogenic signaling and transformation. Project 3 will use peptide hits from phage display libraries, and combinatorial libraries to disrupt STAT3 dimerization, DNA binding activity and to block STAT3 oncogenic signaling and cell transformation. Project 4 will use peptides from phage display peptide libraries and combinatorial libraries synthesized by project 1 to inhibit the activities of CDK4-cyclin D1 and CDK2-cyclin A complexes and to disrupt CDK signaling to down-stream effectors such as the tumor suppressor Rb. Results from the structure activity relationship studies carried out evaluated by projects 2, 3 and 4 will be fed back to project 1 for further optimization of lead compounds which will then be evaluated for their ability to inhibit proliferation, promote apoptosis and block the growth in nude mice of human tumors where RTK, STAT and/or CDK pathways are aberrantly activated. The work described in this program project will enhance our understanding of the role of RTK, STAT and CDK in human cancer and ultimately will result in the discovery of novel anti-cancer drugs that will broaden the spectrum of human tumors that can be treated successfully.