An Inhibitor of NEDD8-activating Enzyme As a New Approach to Treat Cancer

Overview

Journal Nature

Specialty Science

Date 2009 Apr 11

PMID 19360080

Citations 1095

Authors

Teresa A Soucy

Peter G Smith

Michael A Milhollen

Allison J Berger

James M Gavin

Sharmila Adhikari

James E Brownell

Kristine E Burke

David P Cardin

Stephen Critchley

Courtney A Cullis

Amanda Doucette

James J Garnsey

Jeffrey L Gaulin

Rachel E Gershman

Anna R Lublinsky

Alice McDonald

Hirotake Mizutani

Usha Narayanan

Edward J Olhava

Stephane Peluso

Mansoureh Rezaei

Michael D Sintchak

Tina Talreja

Michael P Thomas

Tary Traore

Stepan Vyskocil

Gabriel S Weatherhead

Jie Yu

Julie Zhang

Lawrence R Dick

Christopher F Claiborne

Mark Rolfe

Joseph B Bolen

Steven P Langston

Affiliations

Soon will be listed here.

Abstract

The clinical development of an inhibitor of cellular proteasome function suggests that compounds targeting other components of the ubiquitin-proteasome system might prove useful for the treatment of human malignancies. NEDD8-activating enzyme (NAE) is an essential component of the NEDD8 conjugation pathway that controls the activity of the cullin-RING subtype of ubiquitin ligases, thereby regulating the turnover of a subset of proteins upstream of the proteasome. Substrates of cullin-RING ligases have important roles in cellular processes associated with cancer cell growth and survival pathways. Here we describe MLN4924, a potent and selective inhibitor of NAE. MLN4924 disrupts cullin-RING ligase-mediated protein turnover leading to apoptotic death in human tumour cells by a new mechanism of action, the deregulation of S-phase DNA synthesis. MLN4924 suppressed the growth of human tumour xenografts in mice at compound exposures that were well tolerated. Our data suggest that NAE inhibitors may hold promise for the treatment of cancer.

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References

Bohnsack R, Haas A . Conservation in the mechanism of Nedd8 activation by the human AppBp1-Uba3 heterodimer. J Biol Chem. 2003; 278(29):26823-30. DOI: 10.1074/jbc.M303177200. View

Wilkinson K . The discovery of ubiquitin-dependent proteolysis. Proc Natl Acad Sci U S A. 2005; 102(43):15280-2. PMC: 1266097. DOI: 10.1073/pnas.0504842102. View

Chiba T, Tanaka K . Cullin-based ubiquitin ligase and its control by NEDD8-conjugating system. Curr Protein Pept Sci. 2004; 5(3):177-84. DOI: 10.2174/1389203043379783. View

Saxena S, Dutta A . Geminin and p53: deterrents to rereplication in human cancer cells. Cell Cycle. 2003; 2(4):283-6. View

Machida Y, Hamlin J, Dutta A . Right place, right time, and only once: replication initiation in metazoans. Cell. 2005; 123(1):13-24. DOI: 10.1016/j.cell.2005.09.019. View

Walden H, Podgorski M, Schulman B . Insights into the ubiquitin transfer cascade from the structure of the activating enzyme for NEDD8. Nature. 2003; 422(6929):330-4. DOI: 10.1038/nature01456. View

Vaziri C, Saxena S, Jeon Y, Lee C, Murata K, Machida Y . A p53-dependent checkpoint pathway prevents rereplication. Mol Cell. 2003; 11(4):997-1008. DOI: 10.1016/s1097-2765(03)00099-6. View

Kane R, Dagher R, Farrell A, Ko C, Sridhara R, Justice R . Bortezomib for the treatment of mantle cell lymphoma. Clin Cancer Res. 2007; 13(18 Pt 1):5291-4. DOI: 10.1158/1078-0432.CCR-07-0871. View

Carrano A, Eytan E, Hershko A, Pagano M . SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27. Nat Cell Biol. 1999; 1(4):193-9. DOI: 10.1038/12013. View

10.

Donzelli M, Squatrito M, Ganoth D, Hershko A, Pagano M, Draetta G . Dual mode of degradation of Cdc25 A phosphatase. EMBO J. 2002; 21(18):4875-84. PMC: 126287. DOI: 10.1093/emboj/cdf491. View

11.

Melixetian M, Ballabeni A, Masiero L, Gasparini P, Zamponi R, Bartek J . Loss of Geminin induces rereplication in the presence of functional p53. J Cell Biol. 2004; 165(4):473-82. PMC: 2172361. DOI: 10.1083/jcb.200403106. View

12.

Nishitani H, Sugimoto N, Roukos V, Nakanishi Y, Saijo M, Obuse C . Two E3 ubiquitin ligases, SCF-Skp2 and DDB1-Cul4, target human Cdt1 for proteolysis. EMBO J. 2006; 25(5):1126-36. PMC: 1409712. DOI: 10.1038/sj.emboj.7601002. View

13.

Hu J, McCall C, Ohta T, Xiong Y . Targeted ubiquitination of CDT1 by the DDB1-CUL4A-ROC1 ligase in response to DNA damage. Nat Cell Biol. 2004; 6(10):1003-9. DOI: 10.1038/ncb1172. View

14.

Handeli S, Weintraub H . The ts41 mutation in Chinese hamster cells leads to successive S phases in the absence of intervening G2, M, and G1. Cell. 1992; 71(4):599-611. DOI: 10.1016/0092-8674(92)90594-3. View

15.

Hershko A . The ubiquitin system for protein degradation and some of its roles in the control of the cell division cycle. Cell Death Differ. 2005; 12(9):1191-7. DOI: 10.1038/sj.cdd.4401702. View

16.

Winston J, Strack P, Chu C, Elledge S, Harper J . The SCFbeta-TRCP-ubiquitin ligase complex associates specifically with phosphorylated destruction motifs in IkappaBalpha and beta-catenin and stimulates IkappaBalpha ubiquitination in vitro. Genes Dev. 1999; 13(3):270-83. PMC: 316433. DOI: 10.1101/gad.13.3.270. View

17.

Kane R, Bross P, Farrell A, Pazdur R . Velcade: U.S. FDA approval for the treatment of multiple myeloma progressing on prior therapy. Oncologist. 2003; 8(6):508-13. DOI: 10.1634/theoncologist.8-6-508. View

18.

Kobayashi A, Kang M, Okawa H, Ohtsuji M, Zenke Y, Chiba T . Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2. Mol Cell Biol. 2004; 24(16):7130-9. PMC: 479737. DOI: 10.1128/MCB.24.16.7130-7139.2004. View

19.

Lovejoy C, Lock K, Yenamandra A, Cortez D . DDB1 maintains genome integrity through regulation of Cdt1. Mol Cell Biol. 2006; 26(21):7977-90. PMC: 1636754. DOI: 10.1128/MCB.00819-06. View

20.

Lin J, Dutta A . ATR pathway is the primary pathway for activating G2/M checkpoint induction after re-replication. J Biol Chem. 2007; 282(42):30357-62. DOI: 10.1074/jbc.M705178200. View