Skip to main content
SpringerLink
Log in

Approaches to Discovering Drugs that Regulate E3 Ubiquitin Ligases

  • Conference paper
  • First Online:
The Ubiquitin System in Health and Disease

Part of the book series: Ernst Schering Foundation Symposium Proceedings ((SCHERING FOUND,volume 2008/1))

Abstract

The ubiquitin-proteasome system (UPS) plays an essential role in a wide variety of cell regulatory signaling pathways. The clinical effectiveness of the proteasome inhibitor Velcade in the treatment of several human cancers underscores the importance of the UPS as a novel target area for pharmaceutical intervention. E3 ubiquitin ligases are key enzyme complexes that regulate and determine the ubiquitination of specific substrates, whose abnormal regulation has been implicated in multiple disease phenotypes. Targeting a selective E3 ligase may allow specific manipulation of distinct pathways and eventually lead to a better therapeutic index with reduced nonspecific side effects. Here, we aim to discuss the challenges of interfering with small molecules in this target class, as well as current strategies and progress in E3 ligase drug discovery.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Bodine SC, Latres E, Baumhueter S, Lai VK, Nunez L, Clarke BA, Poueymirou WT, Panaro FJ, Na E, Dharmarajan K, Pan ZQ, Valenzuela DM, DeChiara TM, Stitt TN, Yancopoulos GD, Glass DJ (2001) Identification of ubiquitin ligases required for skeletal muscle atrophy. Science 294:1704–1708

    Article  CAS  PubMed  Google Scholar 

  • Bowman AL, Nikolovska-Coleska Z, Zhong H, Wang S, Carlson HA (2007) Small molecule inhibitors of the MDM2-p53 interaction discovered by ensemble-based receptor models. J Am Chem Soc 129:12809–12814

    Article  CAS  PubMed  Google Scholar 

  • Cardozo T, Abagyan R (2005) Druggability of SCF ubiquitin ligase-protein interfaces. Methods Enzymol 399:634–653

    Article  CAS  PubMed  Google Scholar 

  • Carrano AC, Eytan E, Hershko A, Pagano M (1999) SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27. Nat Cell Biol 4:193–199

    Article  CAS  Google Scholar 

  • Chen J, Marechal V, Levine AJ (1993) Mapping of the p53 and mdm-2 interaction domains. Mol Cell Biol 13:4107–4114

    CAS  PubMed  Google Scholar 

  • Chen Q, Xie W, Kuhn DJ, Voorhees PM, Lopez-Girona A, Mendy D, Corral LG, Krenitsky VP, Xu W, Moutouh-de Parseval L, Webb DR, Mercurio F, Nakayama KI, Nakayama K, Orlowski RZ (2008) Targeting the p27 E3 ligase SCFSkp2 results in p27- and Skp2-mediated cell cycle arrest, and activation of autophagy. Blood 111:4690–4699

    Article  CAS  PubMed  Google Scholar 

  • Davydov IV, Woods D, Safiran YJ, Oberoi P, Fearnhead HO, Fang S, Jensen JP, Weissman AM, Kenten JH, Vousden KH (2004) Assay for ubiquitin ligase activity: high-throughput screen for inhibitors of HDM2. J Biomol Screen 8:695–703

    Article  CAS  Google Scholar 

  • Ding K, Lu Y, Nikolovska-Coleska Z, Wang G, Qiu S, Shangary S, Gao W, Qin D, Stuckey J, Krajewski K, Roller PP, Wang S (2006) Structure-based design of spiro oxindoles as potent, specific small-molecule inhibitors of the MDM2–p53 interaction. J Med Chem 49:3432–3435

    Article  CAS  PubMed  Google Scholar 

  • Gomes MD, Lecker SH, Jagoe RT, Navon A, Goldberg AL (2001) Atrogin-1, a muscle-specific F-box protein highly expressed during muscle atrophy. Proc Natl Acad Sci U S A 98:14440–14445

    Article  CAS  PubMed  Google Scholar 

  • Hao B, Zheng N, Schulman BA, Wu G, Miller JJ, Pagano M, Pavletich NP (2005) Structural basis of the Cks1-dependent recognition of p27(Kip1) by the SCF(Skp2) ubiquitin ligase. Mol Cell 20:9–19

    Article  CAS  PubMed  Google Scholar 

  • Haupt Y, Maya R, Kazaz A, Oren M (1997) Mdm2 promotes the rapid degradation of p53. Nature 387:296–299

    Article  CAS  PubMed  Google Scholar 

  • Hong CA, Swearingen E, Mallari R, Gao X, Cao Z, North A, Young SW, Huang SG (2003) Development of a high throughput time-resolved fluorescence resonance energy transfer assay for TRAF6 ubiquitin polymerization. Assay Drug Dev Technol 1:175–180

    Article  CAS  PubMed  Google Scholar 

  • Huang J, Sheung J, Dong G, Coquilla C, Daniel-Issakani S, Payan DG (2005) High-throughput screening for inhibitors of the e3 ubiquitin ligase APC. Methods Enzymol 399:740–754

    Article  CAS  PubMed  Google Scholar 

  • Huang KS, Vassilev LT (2005) High-throughput screening for inhibitors of the Cks1-Skp2 interaction. Methods Enzymol 399:717–728

    Article  CAS  PubMed  Google Scholar 

  • Issaeva N, Bozko P, Enge M, Protopopova M, Verhoef LG, Masucci M, Pramanik A, Selivanova G (2004) Small molecule RITA binds to p53, blocks p53-HDM-2 interaction and activates p53 function in tumors. Nat Med 10:1321–1328

    Article  CAS  PubMed  Google Scholar 

  • Kamura T, Sato S, Iwai K, Czyzyk-Krzeska M, Conaway RC, Conaway JW (2000) Activation of HIF1alpha ubiquitination by a reconstituted von Hippel-Lindau (VHL) tumor suppressor complex. Proc Natl Acad Sci U S A 97:10430–10435

    Article  CAS  PubMed  Google Scholar 

  • Kussie PH, Gorina S, Marechal V, Elenbaas B, Moreau J, Levine AJ, Pavletich NP (1996) Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain. Science 274:948–953

    Article  CAS  PubMed  Google Scholar 

  • Lai Z, Yang T, Kim YB, Sielecki TM, Diamond MA, Strack P, Rolfe M, Caligiuri M, Benfield PA, Auger KR, Copeland RA (2002) Differentiation of Hdm2-mediated p53 ubiquitination and Hdm2 autoubiquitination activity by small molecular weight inhibitors. Proc Natl Acad Sci U S A 99:14734–14739

    Article  CAS  PubMed  Google Scholar 

  • Lu Y, Nikolovska-Coleska Z, Fang X, Gao W, Shangary S, Qiu S, Qin D, Wang S (2006) Discovery of a nanomolar inhibitor of the human murine double minute 2 (MDM2)-p53 interaction through an integrated, virtual database screening strategy. J Med Chem 49:3759–3762

    Article  CAS  PubMed  Google Scholar 

  • Petersen SL, Wang L, Yalcin-Chin A, Li L, Peyton M, Minna J, Harran P, Wang X (2007) Autocrine TNFalpha signaling renders human cancer cells susceptible to Smac-mimetic-induced apoptosis. Cancer Cell 12:445–456

    Article  CAS  PubMed  Google Scholar 

  • Picksley SM, Vojtesek B, Sparks A, Lane DP (1994) Immunochemical analysis of the interaction of p53 with MDM 2; mapping of the MDM 2 binding site on p53 using synthetic peptides. Oncogene 9:2523–2529

    CAS  PubMed  Google Scholar 

  • Schimmer AD, Dalili S, Batey RA, Riedl SJ (2006) Targeting XIAP for the treatment of malignancy. Cell Death Differ 13:179–188

    Article  CAS  PubMed  Google Scholar 

  • Tsvetkov LM, Yeh KH, Lee SJ, Sun H, Zhang H (1999) p27(Kip1) ubiquitination and degradation is regulated by the SCF(Skp2) complex through phosphorylated Thr187 in p27. Curr Biol 9:661–664

    Article  CAS  PubMed  Google Scholar 

  • Tsvetkov L, Lin H, Sheung J, Zhou X, Dong G, Daniel-Issakani S, Payan D, Huang J (2008) Identification of novel SCF inhibitors. AACR-Ubiquitin conference (in press)

    Google Scholar 

  • Varfolomeev E, Blankenship JW, Wayson SM, Fedorova AV, Kayagaki N, Garg P, Zobel K, Dynek JN, Elliott LO, Wallweber HJ, Flygare JA, Fairbrother WJ, Deshayes K, Dixit VM, Vucic D (2007) IAP antagonists induce autoubiquitination of c-IAPs, NF-kappaB activation, and TNFalpha-dependent apoptosis. Cell 131:669–681

    Article  CAS  PubMed  Google Scholar 

  • Vassilev LT, Vu BT, Graves B, Carvajal D, Podlaski F, Filipovic Z, Kong N, Kammlott U, Lukacs C, Klein C, Fotouhi N, Liu EA (2004) In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 303:844–848

    Article  CAS  PubMed  Google Scholar 

  • Vince JE, Wong WW, Khan N, Feltham R, Chau D, Ahmed AU, Benetatos CA, Chunduru SK, Condon SM, McKinlay M, Brink R, Leverkus M, Tergaonkar V, Schneider P, Callus BA, Koentgen F, Vaux DL, Silke J (2007) IAP antagonists target cIAP1 to induce TNFalpha-dependent apoptosis. Cell 131:682–693

    Article  CAS  PubMed  Google Scholar 

  • Wells JA, McClendon CL (2007) Reaching for high-hanging fruit in drug discovery at protein-protein interfaces. Nature 450:1001–1009

    Article  CAS  PubMed  Google Scholar 

  • Winston JT, Strack P, Beer-Romero P, Chu CY, Elledge SJ, Harper JW (1999) 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 13:270–283

    Article  CAS  PubMed  Google Scholar 

  • Wu G, Chai J, Suber TL, Wu JW, Du C, Wang X, Shi Y (2000) Structural basis of IAP recognition by Smac/DIABLO. Nature 408:1008–1012

    Article  CAS  PubMed  Google Scholar 

  • Xu K, Belunis C, Chu W, Weber D, Podlaski F, Huang KS, Reed SI, Vassilev LT (2003) Protein-protein interactions involved in the recognition of p27 by E3 ubiquitin ligase. Biochem J 371:957–964

    Article  CAS  PubMed  Google Scholar 

  • Xu S, Patel P, Abbasian M, Giegel D, Xie W, Mercurio F, Cox S (2005) In vitro SCFbeta-Trcp1-mediated IkappaBalpha ubiquitination assay for high-throughput screen. Methods Enzymol 399:729–740

    Article  CAS  PubMed  Google Scholar 

  • Yang Y, Ludwig RL, Jensen JP, Pierre SA, Medaglia MV, Davydov IV, Safiran YJ, Oberoi P, Kenten JH, Phillips AC, Weissman AM, Vousden KH (2005) Small molecule inhibitors of HDM 2 ubiquitin ligase activity stabilize and activate p53 in cells. Cancer Cell 6:547–559

    Article  CAS  Google Scholar 

  • Yang Y, Kitagaki J, Dai RM, Tsai YC, Lorick KL, Ludwig RL, Pierre SA, Jensen JP, Davydov IV, Oberoi P, Li CC, Kenten JH, Beutler JA, Vousden KH, Weissman AM (2007) Inhibitors of ubiquitin-activating enzyme (E1), a new class of potential cancer therapeutics. Cancer Res 67:9472–9481

    Article  CAS  PubMed  Google Scholar 

  • Yu X, Yu Y, Liu B, Luo K, Kong W, Mao P, Yu XF (2003) Induction of APOBEC3G ubiquitination and degradation by an HIV-1 Vif-Cul5-SCF complex. Science 302:1056–1060

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Rigel Pharmaceuticals, Inc., 1180 Veterans Boulevard, South San Francisco, CA, 94080, USA

    J. Huang, L. Tsvetkov, K. Qu, S. Daniel-Issakani & D. G. Payan

Authors
  1. J. Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. L. Tsvetkov
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. K. Qu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S. Daniel-Issakani
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. D. G. Payan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J. Huang .

Editor information

S. Jentsch B. Haendler

Rights and permissions

Reprints and permissions

Copyright information

© 2008 Springer-Verlag

About this paper

Cite this paper

Huang, J., Tsvetkov, L., Qu, K., Daniel-Issakani, S., Payan, D.G. (2008). Approaches to Discovering Drugs that Regulate E3 Ubiquitin Ligases. In: Jentsch, S., Haendler, B. (eds) The Ubiquitin System in Health and Disease. Ernst Schering Foundation Symposium Proceedings, vol 2008/1. Springer, Berlin, Heidelberg. https://doi.org/10.1007/2789_2008_107

Download citation

  • DOI: https://doi.org/10.1007/2789_2008_107

  • Published:

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-540-85106-6

  • Online ISBN: 978-3-540-85107-3

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation