Discovery of inhibitors that elucidate the role of UCH-L1 activity in the H1299 lung cancer cell line

Yichin Liu, Hilal A. Lashuel, Sungwoon Choi, Xuechao Xing, April Case, Jake Ni, Li An Yeh, Gregory D. Cuny, Ross L. Stein, Peter T. Lansbury

Research output: Contribution to journalArticle

167 Citations (Scopus)

Abstract

Neuronal ubiquitin C-terminal hydrolase (UCH-L1) has been linked to Parkinson's disease (PD), the progression of certain nonneuronal tumors, and neuropathic pain. Certain lung tumor-derived cell lines express UCH-L1 but it is not expressed in normal lung tissue, suggesting that this enzyme plays a role in tumor progression, either as a trigger or as a response. Small-molecule inhibitors of UCH-L1 would be helpful in distinguishing between these scenarios. By utilizing high-throughput screening (HTS) to find inhibitors and traditional medicinal chemistry to optimize their affinity and specificity, we have identified a class of isatin O-acyl oximes that selectively inhibit UCH-L1 as compared to its systemic isoform, UCH-L3. Three representatives of this class (30, 50, 51) have IC50 values of 0.80-0.94 μM for UCH-L1 and 17-25 μM for UCH-L3. The Ki of 30 toward UCH-L1 is 0.40 μM and inhibition is reversible, competitive, and active site directed. Two isatin oxime inhibitors increased proliferation of the H1299 lung tumor cell line but had no effect on a lung tumor line that does not express UCH-L1. Inhibition of UCH-L1 expression in the H1299 cell line using RNAi had a similar proproliferative effect, suggesting that the UCH-L1 enzymatic activity is antiproliferative and that UCH-L1 expression may be a response to tumor growth. The molecular mechanism of this response remains to be determined.

Original languageEnglish
Pages (from-to)837-846
Number of pages10
JournalChemistry and Biology
Volume10
Issue number9
DOIs
Publication statusPublished - 1 Sep 2003
Externally publishedYes

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Tumors
Lung Neoplasms
Cells
Isatin
Cell Line
Lung
Oximes
Tumor Cell Line
Neoplasms
Ubiquitin Thiolesterase
Pharmaceutical Chemistry
Neuralgia
RNA Interference
Inhibitory Concentration 50
Parkinson Disease
Disease Progression
Catalytic Domain
Protein Isoforms
Screening
Enzymes

ASJC Scopus subject areas

  • Organic Chemistry

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Discovery of inhibitors that elucidate the role of UCH-L1 activity in the H1299 lung cancer cell line. / Liu, Yichin; Lashuel, Hilal A.; Choi, Sungwoon; Xing, Xuechao; Case, April; Ni, Jake; Yeh, Li An; Cuny, Gregory D.; Stein, Ross L.; Lansbury, Peter T.

In: Chemistry and Biology, Vol. 10, No. 9, 01.09.2003, p. 837-846.

Research output: Contribution to journalArticle

Liu, Y, Lashuel, HA, Choi, S, Xing, X, Case, A, Ni, J, Yeh, LA, Cuny, GD, Stein, RL & Lansbury, PT 2003, 'Discovery of inhibitors that elucidate the role of UCH-L1 activity in the H1299 lung cancer cell line', Chemistry and Biology, vol. 10, no. 9, pp. 837-846. https://doi.org/10.1016/j.chembiol.2003.08.010
Liu, Yichin ; Lashuel, Hilal A. ; Choi, Sungwoon ; Xing, Xuechao ; Case, April ; Ni, Jake ; Yeh, Li An ; Cuny, Gregory D. ; Stein, Ross L. ; Lansbury, Peter T. / Discovery of inhibitors that elucidate the role of UCH-L1 activity in the H1299 lung cancer cell line. In: Chemistry and Biology. 2003 ; Vol. 10, No. 9. pp. 837-846.
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