8EMU

Human Carbonic Anhydrase II Heterobifunctional Degraders

Summary for 8EMU

• Entry DOI: 10.2210/pdb8emu/pdb
• Descriptor: Carbonic anhydrase 2, ZINC ION, N-(2-methoxyethyl)-4-sulfamoylbenzamide, ... (5 entities in total)
• Functional Keywords: targeted protein degrader, protac, metalloenzyme, lyase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 30192.76

Authors

Kohlbrand, A.J.,O'Herin, C.B. (deposition date: 2022-09-28, release date: 2023-02-15, Last modification date: 2023-10-25)

Primary citation

O'Herin, C.B.,Moriuchi, Y.W.,Bemis, T.A.,Kohlbrand, A.J.,Burkart, M.D.,Cohen, S.M.
Development of Human Carbonic Anhydrase II Heterobifunctional Degraders.
J.Med.Chem., 66:2789-2803, 2023

PubMed Abstract: 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.

PubMed: 36735827
DOI: 10.1021/acs.jmedchem.2c01843

Experimental method

X-RAY DIFFRACTION (1.13 Å)