Discovery of First-in-Class Carbonic Anhydrase/Histone Deacetylase Dual Inhibitors with Antiproliferative Activity in Cancer Cells

This study reports in vitro evidence supporting a new class of compounds capable of independently targeting the tumor-associated human (h) carbonic anhydrase (CA; EC 4.2.1.1) and histone deacetylase (HDAC; EC 3.5.1.98) isoforms as first-in-class agents endowed with enhanced antiproliferative effects and safety profiles when compared to their constitutive counterparts as well as to clinically used drugs. The binding modes of both the CA- and HDAC-directed moieties were investigated through X-ray and molecular modeling experiments, respectively, thus delivering detailed Structure–Activity Relationship (SAR) knowledge.