The primary aims of project 1 will be to develop new approaches for generating structural diversity in bioactive molecules and to target these compound libraries to critical targets in cell cycle control pathways. Our overriding theme will be to take peptide sequences or protein domains that have been identified either from knowledge of the biological target or from screening of phage display libraries and, by systematic application of novel combinatorial methods, to reduce them to highly potent, bioavailable and in vivo active anti-tumor agents. To do this we will develop several approaches to the facile generation of large combinatorial libraries of potentially active compounds and then apply each of these to the identification of lead structures for disruption of thee key steps in cell cycle control; receptor tyrosine kinase (CDK) function, signal transducers, and activators of transcription (STAT) signaling and cyclin dependent kinase (CDK) activity. Our approach to RTK inhibitors will exploit two strategies involving the design of protein surface binding agents and the construction of libraries of small heterocyclic derivatives of 2-phenylsulfenylindole. In the STAT area we will use solid phase parallel synthesis to prepare libraries of peptidomimetics that block the SH-2 domain of STAT3. With the CDKs we will develop libraries of mimics of key helical domains on the surface of the natural inhibitors, p16 and p21, as well as small heterocyclic derivatives that compete with ATP for binding to the enzyme active site. Screening of the libraries against these key steps in the cell cycle signaling pathways will be carried out in collaboration with Projects 2, 3, and 4. Our primary focus will be the identification and optimization of novel inhibitors for RTKs (including platelet derived growth factor receptor, epidermal growth factor receptor and ErbB2), the STAT family of proteins (with particular focus on STAT3) and the three principal cyclin dependent kinases (CDK2, CDK4 and CDK6).
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