- Activity-based protein profiling reveals deubiquitinase and aldehyde dehydrogenase targets of a cyanopyrrolidine probe
-
Ubiquitin carboxy-terminal hydrolase L1 (UCHL1), a deubiquitinating enzyme (DUB), is a potential drug target in various cancers, and liver and lung fibrosis. However, bona fide functions and substrates of UCHL1 remain poorly understood. Herein, we report the characterization of UCHL1 covalent inhibitor MT16-001 based on a thiazole cyanopyrrolidine scaffold. In combination with chemical proteomics, a closely related activity-based probe (MT16-205) was used to generate a comprehensive quantitative profile for on- and off-targets at endogenous cellular abundance. Both compounds are selective for UCHL1 over other DUBs in intact cells but also engage a range of other targets with good selectivity over the wider proteome, including aldehyde dehydrogenases, redox-sensitive Parkinson's disease related protein PARK7, and glutamine amidotransferase. Taken together, these results underline the importance of robust profiling of activity-based probes as chemical tools and highlight the cyanopyrrolidine warhead as a versatile platform for liganding diverse classes of protein with reactive cysteine residues which can be used for further inhibitor screening, and as a starting point for inhibitor development. This journal is
- Elkhalifa, Sarah,Harrigan, Jeanine A.,Mason, Katie,Panyain, Nattawadee,Smith, Lisa M.,Tate, Edward W.,Thawani, Aditya Raymond,Godinat, Aurélien,Lachiondo-Ortega, Sofía
-
supporting information
p. 1935 - 1943
(2021/12/16)
-
- AMINOTHIAZOLE COMPOUNDS AS C-KIT INHIBITORS
-
The invention relates to c-Kit inhibitors useful in the treatment of cancers, and other -threonine kinase mediated diseases, having the Formula: (I) wherein A, L, R1, R2, R3, and n are described herein.
- -
-
Paragraph 00262
(2018/07/05)
-
- N1 -(4-(5-(CYCLOPROPYLMETHYL)-1 -METHYL-1 H-PYRAZOL-4-YL)PYRIDIN-2-YL)CYCLOHEXANE-1,4-DIAMINE DERIVATIVES AND RELATED COMPOUNDS AS CK1 AND/OR IRAKI INHIBITORS FOR TREATING CANCER
-
The present invention provides pyrazole derivatives of Formula (I), and in particular N1-(4-(5-(cyclopropylmethyl)-1-methyl-lH-pyrazol-4-yl)pyridin-2-yl)cyclohexane-1,4-diamine derivatives and related compounds as casein kinase 1 (CK1) and/or interleukin 1 receptor associated kinase 1 (IRAKI) inhibitors for treating cancer, inflammatory and immune related disorders.
- -
-
Page/Page column 36; 37
(2018/08/26)
-
- N-(5-MEMBERED AROMATIC RING)-AMIDO ANTI-VIRAL COMPOUNDS
-
Disclosed are compounds having Formula (I) and the compositions and methods thereof for treating or preventing a viral infection mediated at least in part by a virus in the Flaviviridae family of viruses, wherein A, R2, m, R, V, W, T, Z, R
- -
-
Page/Page column 105
(2008/06/13)
-
- Investigations of the halogen dance reaction on N-substituted 2-thiazolamines
-
(Chemical Equation Presented) The halogen dance (HD) reaction on various 2-thiazolamine systems was investigated providing an easy access to a series of 5-substituted 4-bromo-2-thiazolamine derivatives. We could show that HD is a very favored process for
- Stanetty, Peter,Schnuerch, Michael,Mereiter, Kurt,Mihovilovic, Marko D.
-
p. 567 - 574
(2007/10/03)
-