8EDE

Crystal structure of covalent inhibitor 2-chloro-N'-(N-(4-chlorophenyl)-N-methylglycyl)acetohydrazide bound to Ubiquitin C-terminal Hydrolase-L1

8EDE の概要

• エントリーDOI: 10.2210/pdb8ede/pdb
• 分子名称: Ubiquitin carboxyl-terminal hydrolase isozyme L1, 2-[(4-chlorophenyl)-methyl-amino]-~{N}'-ethanoyl-ethanehydrazide, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: uchl1, deubiquitylating enzyme, inhibitor, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 50606.34

構造登録者

Patel, R.,Imhoff, R.,Flaherty, D.,Das, C. (登録日: 2022-09-04, 公開日: 2023-09-20, 最終更新日: 2026-03-04)

主引用文献

Imhoff, R.D.,Patel, R.,Safdar, M.H.,Jones, H.B.L.,Pinto-Fernandez, A.,Vendrell, I.,Chen, H.,Muli, C.S.,Krabill, A.D.,Kessler, B.M.,Wendt, M.K.,Das, C.,Flaherty, D.P.
Covalent Fragment Screening and Optimization Identifies the Chloroacetohydrazide Scaffold as Inhibitors for Ubiquitin C-terminal Hydrolase L1.
J.Med.Chem., 67:4496-4524, 2024

PubMed Abstract: Dysregulation of the ubiquitin-proteasome systems is a hallmark of various disease states including neurodegenerative diseases and cancer. Ubiquitin C-terminal hydrolase L1 (UCHL1), a deubiquitinating enzyme, is expressed primarily in the central nervous system under normal physiological conditions, however, is considered an oncogene in various cancers, including melanoma, lung, breast, and lymphoma. Thus, UCHL1 inhibitors could serve as a viable treatment strategy against these aggressive cancers. Herein, we describe a covalent fragment screen that identified the chloroacetohydrazide scaffold as a covalent UCHL1 inhibitor. Subsequent optimization provided an improved fragment with single-digit micromolar potency against UCHL1 and selectivity over the closely related UCHL3. The molecule demonstrated efficacy in cellular assays of metastasis. Additionally, we report a ligand-bound crystal structure of the most potent molecule in complex with UCHL1, providing insight into the binding mode and information for future optimization.

PubMed: 38488146
DOI: 10.1021/acs.jmedchem.3c01661

実験手法

X-RAY DIFFRACTION (1.799 Å)