Recent studies have shown that TGF-IS inhibits cell proliferation by blocking cell cycle progression at the G1phase of the cell cycle and hence, is thought to function as a tumor suppressor protein. Most human cancersappear to have lost their growth-inhibitory response to TGF-U. Our preliminary studies show that foregutcancers with inactivation of TGF-I3 signaling express high levels of cyclin D1 and CDK4 levels, suggestingthat the deregulated expression of these proteins may contribute to the development of these tumors.Flavopiridol, an established Cdk inhibitor used in treatment protocols for certain cancers, is known to inhibitmost known CDKs especially against CDKs 7, 8 and 9, is thought to be largely responsible for the toxic sideeffectscaused by this drug in clinical trials. In light of these observations, we have screened a compoundlibrary of kinase inhibitors for CDK-4 specific inhibition and isolated two novel molecules (ON55290 andON27900) which exhibit CDK4 inhibitory activity. In this application, we propose to carry out pre-clinicalstudies to test the usefulness of these molecules in gastrointestinal cancer therapy.
The aims of the proposal are:1. To further validate the role of CDK4 in Elf'', Elf/~:Smad3+/- tumor model system through evaluation oftumor incidence in CDK4+/V Bf1', CDK4+/~: Elf/Elf'-SmadS^ and CDK4+A; Elf /Elf:Smad4+/- mice.2. (a) To expand the chemical library in an effort to understand the structure-activity relationship (SAR) ofCDK4 inhibitors and (b) to conduct a detailed kinetic analysis of CDK4 inhibition by ON55290 and ON27900to gain critical information on the mechanisms by which these compounds elicit their inhibitory effects onCDK4.3. To determine the molecular mechanisms by which ON55290 and ON27900 bring about growth arrest anddeath of human gastrointestinal cancer cells. 4. To assess the safety and pharmacokinetics of the candidatedrug in animal models of gastrointestinal cancers that develop in the TGF-f3 inactivated state.
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