Carbonic anhydrase IX (CAIX) is a zinc membrane metalloenzyme that catalyzes the hydration of carbon dioxide in response to a hypoxic and acidic extracellular environment. It is prevalent in many human cancers including renal cell carcinomas, colorectal, and lung cancer. Its overexpression on the membrane of malignant cells and low expression levels on normal tissues make CAIX a particularly attractive target for small molecule inhibitors, antibody drug conjugates, and small molecule drug conjugates. In this study, small molecule inhibitors were used as targeting moieties and converted to small molecule drug conjugates (SMDCs) through the conjugation of various imaging and therapeutic cargos. Fluorescent SMDCs were used to characterize the in vitro binding affinity and kinetics in several human cancer cell lines that constitutively express CAIX. Near infrared and SPECT/CT SMACs were used in in vivo xenograft models of CAIX to demonstrate the tumor-specific uptake and tissue biodistribution patterns. Finally, the in vitro and in vivo evaluation of CAIX targeted therapeutic tubulysin B SMDCs show the rapid and permanent elimination of tumors in mouse xenograft models.

Design, synthesis, and biological evaluation of small molecule drug conjugates targeting carbonic anhydrase IX positive cancers

254th National Meeting (2017)

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