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Ubiquitin C-Terminal Hydrolase L1: Biochemical and Cellular Characterization of a Covalent Cyanopyrrolidine-Based Inhibitor |
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| Authors: | Aaron D Krabill Hao Chen Dr Sajjad Hussain Dr Chao Feng Dr Ammara Abdullah Prof Chittaranjan Das Dr Uma K Aryal Prof Carol Beth Post Prof Michael K Wendt Prof Paul J Galardy Prof Daniel P Flaherty |
| Affiliation: | 1. Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, 575 Stadium Mall Dr., West Lafayette, IN, 47907 USA;2. Division of Pediatric Hematology–Oncology, Mayo Clinic, 200 First St. SW, Guggenheim 15, Rochester, MN, 55905 USA
Department of Pediatric and Adolescent Medicine, Mayo Clinic, 200 First St. SW, Guggenheim 15, Rochester, MN, 55905 USA;3. Department of Chemistry, College of Science, Purdue University, 560 Oval, West Lafayette, IN, 47907 USA;4. Purdue Proteomics Facility, Bindley Biosciences Center, Purdue University, 1275 3rd St., West Lafayette, IN, 47907 USA;5. Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, 575 Stadium Mall Dr., West Lafayette, IN, 47907 USA Department of Biological Sciences, Markey Center for Structural Biology, Purdue University, 915 W State St., West Lafayette, IN, 47907 USA Purdue Institute for Drug Discovery, 720 Clinic Dr., West Lafayette, IN, 47907 USA Purdue Center for Cancer Research, Hanson Life Sciences Research Building, 201 S University St., West Lafayette, IN, 47907 USA;6. Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, 575 Stadium Mall Dr., West Lafayette, IN, 47907 USA Purdue Institute for Drug Discovery, 720 Clinic Dr., West Lafayette, IN, 47907 USA Purdue Center for Cancer Research, Hanson Life Sciences Research Building, 201 S University St., West Lafayette, IN, 47907 USA;7. Division of Pediatric Hematology–Oncology, Mayo Clinic, 200 First St. SW, Guggenheim 15, Rochester, MN, 55905 USA |
| Abstract: | The deubiquitinase (DUB) ubiquitin C-terminal hydrolase L1 (UCHL1) is expressed primarily in the central nervous system under normal physiological conditions. However, UCHL1 is overexpressed in various aggressive forms of cancer with strong evidence supporting UCHL1 as an oncogene in lung, glioma, and blood cancers. In particular, the level of UCHL1 expression in these cancers correlates with increased invasiveness and metastatic behavior, as well as poor patient prognosis. Although UCHL1 is considered an oncogene with potential as a therapeutic target, there remains a significant lack of useful small-molecule probes to pharmacologically validate in vivo targeting of the enzyme. Herein, we describe the characterization of a new covalent cyanopyrrolidine-based UCHL1 inhibitory scaffold in biochemical and cellular studies to better understand the utility of this inhibitor in elucidating the role of UCHL1 in cancer biology. |
| Keywords: | covalent inhibitors deubiquitinase enzyme inhibition hydrolases structural biology |