8EXC

Human Carbonic Anhydrase II bound tert-butyl (3-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propoxy)butoxy)propyl)carbamate

8EXC の概要

• エントリーDOI: 10.2210/pdb8exc/pdb
• 関連するPDBエントリー: 8EMU
• 分子名称: Carbonic anhydrase 2, N-(3-{4-[3-({2-[(3R)-2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}amino)propoxy]butoxy}propyl)-4-sulfamoylbenzamide, ZINC ION, ... (5 entities in total)
• 機能のキーワード: targeted protein degrader, protac, metalloenzyme, lyase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 30319.88

構造登録者

Kohlbrand, A.J.,O'Herin, C.B. (登録日: 2022-10-25, 公開日: 2023-02-22, 最終更新日: 2023-10-25)

主引用文献

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

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

実験手法

X-RAY DIFFRACTION (1.9 Å)