Development of Human Carbonic Anhydrase II Heterobifunctional Degraders

Human carbonic anhydrase
II (hCAII) is a metalloenzyme
essential
to critical physiological processes in the body. hCA inhibitors are
used clinically for the treatment of indications ranging from glaucoma
to epilepsy. Targeted protein degraders have emerged as a promising
means of inducing the degradation of disease-implicated proteins by
using the endogenous quality control mechanisms of a cell. Here, a
series of heterobifunctional degrader candidates targeting hCAII were
developed from a simple aryl sulfonamide fragment. Degrader candidates
were functionalized to produce either cereblon E3 ubiquitin ligase
(CRBN) recruiting proteolysis targeting chimeras (PROTACs) or adamantyl-based
hydrophobic tags (HyTs). Screens in HEK293 cells identified two PROTAC
small-molecule degraders of hCA. Optimization of linker length and
composition yielded a degrader with sub-nanomolar potency and sustained
depletion of hCAII over prolonged treatments. Mechanistic studies
suggest that this optimized degrader depletes hCAII through the same
mechanism as previously reported CRBN-recruiting heterobifunctional
degraders.