The goals of this core are to evaluate AGT modulators in vivo for AGT- inactivating potency, therapeutic efficacy when combined with BCNU and rat pharmacokinetics. Compounds will be initially screened for AGT- inactivating potency in vitro and in cell culture as described in Core B of this application. Compounds from core B and ester prodrugs with tumor selectivity from Program 2 will be tested in Core C. Data generated from Core C will provide guidance on the further development of compounds in programs 2,3,4 and 5. In the initial year of funding, approximately 3 compounds will be evaluated/year for AGT inactivation and human tumor growth inhibition and 3-5 will be evaluated for rat pharmacokinetics. In the subsequent years of funding, an additional 2 compounds will be evaluated/year. The overall goal is to provide preclinical efficacy data to prioritize compounds with better therapeutic properties than O6- benzylguanine.
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