8EYL
Human Carbonic Anhydrase II with Tert-butyl (2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethyl)carbamate
Summary for 8EYL
| Entry DOI | 10.2210/pdb8eyl/pdb |
| Related | 8EMU 8EXC 8EXG |
| Descriptor | Carbonic anhydrase 2, ZINC ION, MERCURIBENZOIC ACID, ... (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 | 30835.33 |
| Authors | Kohlbrand, A.J.,O'Herin, C.B. (deposition date: 2022-10-27, release date: 2023-02-22, 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., 2023 Cited by 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: 36735827DOI: 10.1021/acs.jmedchem.2c01843 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.18 Å) |
Structure validation
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