Designing carbonic anhydrase inhibitors for the treatment of breast cancer.

INTRODUCTION: Carbonic anhydrase (CA) IX is one of the proteins that are involved in cancerogenesis in hypoxic breast tumors. Indeed, it is present in high amounts in hypoxic tumor cells, where it plays a crucial role in metabolic reprogramming due to the scarcity of oxygen, triggered by the hypoxia inducible factor 1 transcription factor. In such tumors, CA IX is involved, along with other proteins, in tumor pH regulation and its survival in a harsh environment (including hypoxia and acidity). CA IX is also validated as an imaging and treatment target for hypoxic tumors and metastasis. AREAS COVERED: In this review, the authors highlight the wealth of CA IX inhibitors currently in the literature. This includes the two most investigated classes of compounds being the sulfonamides and the coumarins, including their isosteres. EXPERT OPINION: The most advanced CA IX inhibitors candidates, which demonstrate antimetastatic activity in breast cancer, are the sulfonamides, with one compound (SLC-0111) currently in Phase I clinical development. The fact that this first inhibitor has progressed could increase interest in the development of conceptually novel antitumor/antimetastic drugs belonging to the CA inhibitors class.