Synthesis of Small Molecule Vascular Disrupting Agents and Cathepsin B Cleavable Linker to Develop Antibody-Drug Conjugates for Cancer Treatment
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Vascular disrupting agents (VDAs), a subclass of vascular targeting agents (VTAs), represent an emerging therapeutic strategy for targeting tumor vasculature to impart irreversible vessel damage leading to tumor necrosis. Recently discovered VDAs that have demonstrated significant potencies comparable to colchicine and combretastatin A-4 are KGP18 and KGP156, developed by the Pinney Group and coworkers (Baylor University), which utilize a benzosuberene molecular scaffold. KGP18 and KGP156 are both potent inhibitors of tubulin polymerization with IC50 values of approximately 1.4 µM and 1.2 µM, respectively, similar to that of combretastatin A-4 (CA4) which has an IC50 value of 1.0 µM in this assay. These benzosuberene analogues (KGP18 and KGP156) demonstrate potent cytotoxicity against human cancer cell lines (in vitro). Synthetic efforts have been advanced to conjugate these benzosuberene analogues to antibodies, via a conditionally stable linker, in order to produce antibody-drug conjugates (ADCs), which represent a promising class of anticancer therapeutic modalities that selectively target cancer cells (or an antigen in the tumor microenvironment) while leaving healthy cells unharmed. When the ADCs internalize within a target cell, the linker is then cleaved via a mechanism catalyzed by an enzyme or a change in pH. In this study, the benzosuberene analogues KGP18 and KGP156 were synthesized, as well as the linker that is used for the ADC.