Bifunctional compounds for targeted degradation of carbonic anhydrase IX through integrin-facilitated lysosome degradation.

Abstract

As an important therapeutic target, carbonic anhydrase IX (CAIX) is crucial in pH regulation of hypoxic solid tumors, thus keeping the survival of them in acidic microenvironment, and promoting their proliferation, invasion and metastasis. To degrade endogenous CAIX, three bifunctional compounds were designed according to the integrin-facilitated lysosomal degradation (IFLD) strategy. These compounds are composed of a CAIX binding ligand, an integrin-recognizing ligand, connected via a linker, which could induce CAIX degradation in an integrin- and lysosome-dependent manner. Among them, Sul-L1-RGD showed the highest degradation efficacy, and could inhibit the proliferation of tumor cells under hypoxic conditions, thus it has great potential to be applied in cancer drug discovery.