Inhibitors of CA IX Enzyme Based on Polyhedral Boron Compounds

Graphical Abstract

The review covers several classes of inhibitors specific for carbonic anhydrase IX enzyme that emerged recently from a non-traditional concept. This is characterized by combination of space-filing inorganic (metalla)carborane cluster with sulfamide and sulfonamide binding motif for Zn²⁺ in the active site. The structural factors essential for attaining high activity and selectivity for the CA IX isoform are discussed. Results from preclinical studies show relevance of these compounds for development of anticancer drugs.

Abstract

This review describes recent progress in the design and development of inhibitors of human carbonic anhydrase IX (CA IX) based on space-filling carborane and cobalt bis(dicarbollide) clusters. CA IX enzyme is known to play a crucial role in cancer cell proliferation and metastases. The new class of potent and selective CA IX inhibitors combines the structural motif of a bulky inorganic cluster with an alkylsulfamido or alkylsulfonamido anchor group for Zn²⁺ ion in the enzyme active site. Detailed structure-activity relationship (SAR) studies of a large series containing 50 compounds uncovered structural features of the cluster-containing inhibitors that are important for efficient and selective inhibition of CA IX activity. Preclinical evaluation of selected compounds revealed low toxicity, favorable pharmacokinetics and ability to reduce tumor growth. Cluster-containing inhibitors of CA IX can thus be considered as promising candidates for drug development and/or for combination therapy in boron neutron capture therapy (BNCT).