The development of prodrug strategies for the targeted delivery of dihydronaphthalene and benzosuberene inhibitors of tubulin polymerization.
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Ford, Jacob W., 1989-
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The abnormalities present in tumor vasculature provide a promising opportunity for targeted therapeutic approaches. Vascular disrupting agents (VDAs) damage the existing tumor vasculature limiting the delivery of oxygen and nutrients to the tumor and thus inducing necrosis. Inspired by the natural products colchicine and combretastatin A-4/A1(CA4 and CA1), the Pinney Research Group in close collaboration with the Trawick Research Group has assembled a library of structurally diverse inhibitors of tubulin polymerization. In particular, dihydronaphthalene (KGP03, KGP05) and benzosuberene (KGP18, KGP156) were discovered to be potent inhibitors of tubulin polymerization that exhibited nanomolar to picomolar cytotoxicity. To extend structure activity relationship studies of VDAs that bind to the colchicine binding site on tubulin, several structurally diverse chalcones and related analogues were synthesized. Antibody-drug conjugates (ADCs) represent a promising form of targeted therapy in cancer treatment. In this strategy a potent anticancer agent is conjugated to an antibody that is specific for an antigen that is highly expressed on the surface of cancer cells. Drug linker constructs for ADC applications were synthesized containing potent benzosuberene and dihydronaphthalene inhibitors of tubulin polymerization as payloads. A variety of synthetic strategies were developed to incorporate these small-molecule VDAs (as payloads) in drug-linker constructs containing a cathepsin B cleavable linker widely used in ADC research. Tumor hypoxia presents another opportunity for targeted therapies. Bioreductively activatable prodrug constructs (BAPCs) utilize reductase enzyme mediated cleavage to convert an inactive prodrug to its active parent form in areas of pronounced hypoxia in the tumor microenvironment. Lead small-molecule inhibitors of tubulin polymerization KGP18, KGP03, and OXi8006 were incorporated into a series of potential BAPCs containing bioreductive aryl triggers. These prodrugs were evaluated as BAPCs through close collaboration with the Trawick Research Group. Cathepsin L is a protease that is upregulated in many cancers and has been implicated in cancer metastasis. The Pinney and Trawick research groups have developed a series of thiosemicarbazone inhibitors of cathepsin L. Progress towards drug-linker conjugates that feature KGP18 conjugated through self-immolative linkers to a known inhibitor of cathepsin L are reported. Additionally, dipeptides incorporating features of known inhibitors of cathepsin L were explored for selectivity.