Selective and Cell-active Inhibitors of the USP1/ UAF1 Deubiquitinase Complex Reverse Cisplatin Resistance in Non-small Cell Lung Cancer Cells

Overview

Journal Chem Biol

Publisher Elsevier

Specialties Biochemistry
Biology
Chemistry

Date 2011 Nov 29

PMID 22118673

Citations 118

Authors

Junjun Chen

Thomas S Dexheimer

Yongxing Ai

Qin Liang

Mark A Villamil

James Inglese

David J Maloney

Ajit Jadhav

Anton Simeonov

Zhihao Zhuang

Affiliations

Soon will be listed here.

Abstract

Ubiquitin-specific proteases (USPs) have in recent years emerged as a promising therapeutic target class. We identified selective small-molecule inhibitors against a deubiquitinase complex, the human USP1/UAF1, through quantitative high throughput screening (qHTS) of a collection of bioactive molecules. The top inhibitors, pimozide and GW7647, inhibited USP1/UAF1 noncompetitively with a K(i) of 0.5 and 0.7 μM, respectively, and displayed selectivity against a number of deubiquitinases, deSUMOylase, and cysteine proteases. The USP1/UAF1 inhibitors act synergistically with cisplatin in inhibiting cisplatin-resistant non-small cell lung cancer (NSCLC) cell proliferation. USP1/UAF1 represents a promising target for drug intervention because of its involvement in translesion synthesis and Fanconi anemia pathway important for normal DNA damage response. Our results support USP1/UAF1 as a potential therapeutic target and provide an example of targeting the USP/WD40 repeat protein complex for inhibitor discovery.

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References

Simeonov A, Jadhav A, Thomas C, Wang Y, Huang R, Southall N . Fluorescence spectroscopic profiling of compound libraries. J Med Chem. 2008; 51(8):2363-71. DOI: 10.1021/jm701301m. View

Radujkovic A, Schad M, Topaly J, Veldwijk M, Laufs S, Schultheis B . Synergistic activity of imatinib and 17-AAG in imatinib-resistant CML cells overexpressing BCR-ABL--Inhibition of P-glycoprotein function by 17-AAG. Leukemia. 2005; 19(7):1198-206. DOI: 10.1038/sj.leu.2403764. View

Kim J, Parmar K, Huang M, Weinstock D, Ruit C, Kutok J . Inactivation of murine Usp1 results in genomic instability and a Fanconi anemia phenotype. Dev Cell. 2009; 16(2):314-20. PMC: 3134285. DOI: 10.1016/j.devcel.2009.01.001. View

Cohn M, Kowal P, Yang K, Haas W, Huang T, Gygi S . A UAF1-containing multisubunit protein complex regulates the Fanconi anemia pathway. Mol Cell. 2007; 28(5):786-97. DOI: 10.1016/j.molcel.2007.09.031. View

Colland F, Formstecher E, Jacq X, Reverdy C, Planquette C, Conrath S . Small-molecule inhibitor of USP7/HAUSP ubiquitin protease stabilizes and activates p53 in cells. Mol Cancer Ther. 2009; 8(8):2286-95. DOI: 10.1158/1535-7163.MCT-09-0097. View

Wang W . Emergence of a DNA-damage response network consisting of Fanconi anaemia and BRCA proteins. Nat Rev Genet. 2007; 8(10):735-48. DOI: 10.1038/nrg2159. View

Reyes-Turcu F, Ventii K, Wilkinson K . Regulation and cellular roles of ubiquitin-specific deubiquitinating enzymes. Annu Rev Biochem. 2009; 78:363-97. PMC: 2734102. DOI: 10.1146/annurev.biochem.78.082307.091526. View

Guedat P, Colland F . Patented small molecule inhibitors in the ubiquitin proteasome system. BMC Biochem. 2007; 8 Suppl 1:S14. PMC: 2106365. DOI: 10.1186/1471-2091-8-S1-S14. View

Albertella M, Green C, Lehmann A, OConnor M . A role for polymerase eta in the cellular tolerance to cisplatin-induced damage. Cancer Res. 2005; 65(21):9799-806. DOI: 10.1158/0008-5472.CAN-05-1095. View

10.

Chou T, Motzer R, Tong Y, Bosl G . Computerized quantitation of synergism and antagonism of taxol, topotecan, and cisplatin against human teratocarcinoma cell growth: a rational approach to clinical protocol design. J Natl Cancer Inst. 1994; 86(20):1517-24. DOI: 10.1093/jnci/86.20.1517. View

11.

Scheer J, Romanowski M, Wells J . A common allosteric site and mechanism in caspases. Proc Natl Acad Sci U S A. 2006; 103(20):7595-600. PMC: 1458511. DOI: 10.1073/pnas.0602571103. View

12.

Kornacker M, Lai Z, Witmer M, Ma J, Hendrick J, Lee V . An inhibitor binding pocket distinct from the catalytic active site on human beta-APP cleaving enzyme. Biochemistry. 2005; 44(34):11567-73. DOI: 10.1021/bi050932l. View

13.

McGovern S, Helfand B, Feng B, Shoichet B . A specific mechanism of nonspecific inhibition. J Med Chem. 2003; 46(20):4265-72. DOI: 10.1021/jm030266r. View

14.

Oestergaard V, Langevin F, Kuiken H, Pace P, Niedzwiedz W, Simpson L . Deubiquitination of FANCD2 is required for DNA crosslink repair. Mol Cell. 2007; 28(5):798-809. PMC: 2148256. DOI: 10.1016/j.molcel.2007.09.020. View

15.

Zhang , Chung , OLDENBURG . A Simple Statistical Parameter for Use in Evaluation and Validation of High Throughput Screening Assays. J Biomol Screen. 2000; 4(2):67-73. DOI: 10.1177/108705719900400206. View

16.

Strobl J, Kirkwood K, Lantz T, Lewine M, Peterson V, Worley 3rd J . Inhibition of human breast cancer cell proliferation in tissue culture by the neuroleptic agents pimozide and thioridazine. Cancer Res. 1990; 50(17):5399-405. View

17.

Virdee S, Ye Y, Nguyen D, Komander D, Chin J . Engineered diubiquitin synthesis reveals Lys29-isopeptide specificity of an OTU deubiquitinase. Nat Chem Biol. 2010; 6(10):750-7. DOI: 10.1038/nchembio.426. View

18.

Patel K, Joenje H . Fanconi anemia and DNA replication repair. DNA Repair (Amst). 2007; 6(7):885-90. DOI: 10.1016/j.dnarep.2007.02.002. View

19.

Copeland R . Evaluation of enzyme inhibitors in drug discovery. A guide for medicinal chemists and pharmacologists. Methods Biochem Anal. 2005; 46:1-265. View

20.

Bergink S, Jentsch S . Principles of ubiquitin and SUMO modifications in DNA repair. Nature. 2009; 458(7237):461-7. DOI: 10.1038/nature07963. View