Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Pharmaceutical intervention in the JAK/STAT signaling pathway

Oncogene volume 19, pages 2645–2656 (2000)Cite this article

Abstract

Many cytokines exert their effect via the JAK/STAT signal transduction pathway. Due to the medical relevance of many of these cytokines, they are being exploited, either directly, or through antagonists, as therapeutics for a variety of serious diseases. Currently, these therapeutics consist almost entirely of protein products, with all of their attendant drawbacks. Delineation of the signaling mechanisms for the cytokines, however, has allowed the design and implementation of a variety of cell-based and biochemical screens for small molecule mimics or antagonists of these cytokines. Several successful assays will be described along with the advantages of each type of assay. Use of assays of this type should make it possible to discover numerous small molecule cytokine modulators with significant utility in the clinic.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8

Similar content being viewed by others

References

  • Abramovich C, Yakobson B, Chebath J and Revel M . 1997 EMBO J 16: 260–266

  • Ahmed T, Wuest D and Ciavarella D . 1992 J Clin Apheresis 7: 129–131

  • Baselga J, Norton L, Albanell J, Kim YM and Mendelsohn J . 1998 Cancer Res 58: 2825–2831

  • Braunwaler AF, Yarwood DR, Hall T, Missbach M, Lipson KE and Sills MA . 1996 Anal Biochem 234: 23–26

  • Bromberg JF, Wrzeszczynska MH, Devgan G, Zhao Y, Pestell RG, Albanese C and Darnell Jr JE . 1999 Cell 98: 295–303

  • Broudy VC, Lin NL, Buhring HJ, Komatsu N and Kavanagh TJ . 1998 Blood 91: 898–906

  • Catlett-Falcone R, Dalton WS and Jove R . 1999 Curr Opin Oncol 11: 490–496

  • Chen D, Ma H, Hong H, Koh SS, Huang SM, Schurter BT, Aswad DW and Stallcup MR . 1999 Science 284: 2174–2177

  • Chung CD, Liao J, Liu B, Rao X, Jay P, Berta P and Shuai K . 1997 Science 278: 1803–1805

  • Damjanovich S, Bene L, Matko J, Alileche A, Goldman CK, Sharrow S and Waldmann TA . 1997 Proc Natl Acad Sci USA 94: 13134–13139

  • Darnell Jr JE, Kerr IM and Stark GR . 1994 Science 264: 1415–1421

  • Decker T, Kovarik P and Meinke A . 1997 J Interferon Cytokine Res 17: 121–134

  • Durbin JE, Hackenmiller R, Simon MC and Levy DE . 1996 Cell 84: 443–450

  • Eschbach JW, Egrie JC, Downing MR, Browne JK and Adamson JW . 1987 N Engl J Med 316: 73–78

  • Fry DW, Kraker AJ, McMichael A, Ambroso LA, Nelson JM, Leopold WR, Connors RW and Bridges AJ . 1994 Science 265: 1093–1095

  • Fuh G, Cunningham BC, Fukunaga R, Nagata S, Goeddel DV and Wells JA . 1992 Science 256: 1677–1680

  • Giralt S, Kantarjian H and Talpaz M . 1995 Semin Hematol 32: 152–158

  • Goodman PA, Niehoff LB and Uckun FM . 1998 J Biol Chem 273: 17742–17748

  • Greenlund AC, Morales MO, Viviano BL, Yan H, Krolewski J and Schreiber RD . 1995 Immunity 2: 677–687

  • Haspel RL and Darnell Jr JE . 1999 Proc Natl Acad Sci USA 96: 10188–10193

  • Hoofnagle JH . 1990 J Hepatol 11, Suppl 1: S100–S107

  • Horvath CM, Wen Z and Darnell Jr JE . 1995 Genes Dev 9: 984–994

  • Ihle JN . 1995 Adv Immunol 60: 1–35

  • Ihle JN, Witthuhn BA, Quelle FW, Yamamoto K, Thierfelder WE, Kreider B, Silvennoinen O . 1994 Trends Biochem Sci 19: 222–227

  • Kaplan DH, Shankaran V, Dighe AS, Stockert E, Aguet M, Old LJ and Schreiber RD . 1998 Proc Natl Acad Sci USA 95: 7556–7561

  • Kaplan MH, Schindler U, Smiley ST and Grusby MJ . 1996a Immunity 4: 313–319

  • Kaplan MH, Sun YL, Hoey T and Grusby MJ . 1996b Nature 382: 174–177

  • Klingmuller U, Lorenz U, Cantley LC, Neel BG and Lodish HF . 1995 Cell 80: 729–738

  • Kolb A, Burke J and Mathis G . 1997 High Throughput Screening The Discovery of Bioactive Molecules Devlin J ed Marcel Dekker New York pp 345–360

  • Lamb P, Tapley P and Rosen J . 1998 Drug Discovery Today 3: 122–130

  • Lamb P, Seidel HM, Haslam J, Milocco L, Kessler LV, Stein RB and Rosen J . 1995 Nucleic Acids Res 23: 3283–3289

  • Lindsay KL . 1999 J Hepatol, Suppl 1 232–236

  • Liu B, Liao J, Rao X, Kushner SA, Chung CD, Chang DD and Shuai K . 1998 Proc Natl Acad Sci USA 95: 10626–10631

  • Meraz MA, White JM, Sheehan KC, Bach EA, Rodig SJ, Dighe AS, Kaplan DH, Riley JK, Greenlund AC, Campbell D, Carver-Moore K, DuBois RN, Clark R, Aguet M and Schreiber RD . 1996 Cell 84: 431–442

  • Meydan N, Grunberger T, Dadi H, Shahar M, Arpaia E, Lapidot Z, Leeder JS, Freedman M, Cohen A, Gazit A, Levitzki A and Roifman CM . 1996 Nature 379: 645–648

  • Moreland LW, Baumgartner SW, Schiff MH, Tindall EA, Fleischmann RM, Weaver AL, Ettlinger RE, Cohen S, Koopman WJ, Mohler K, Widmer MB and Blosch CM . 1997 N Engl J Med 337: 141–147

  • Moriggl R, Sexl V, Piekorz R, Topham D and Ihle JN . 1999 Immunity 11: 225–230

  • Nasir MS and Jolley ME . 1999 Comb Chem High Throughput Screen 2: 177–190

  • Nemunaitis J, Singer JW, Buckner CD, Hill R, Storb R, Thomas ED and Appelbaum FR . 1998 Blood 72: 834–836

  • Panitch HS . 1995 Mult Scler 1Suppl 1: S17–S21

  • Quelle FW, Thierfelder W, Witthuhn BA, Tang B, Cohen S and Ihle JN . 1995 J Biol Chem 270: 20775–20780

  • Racker E . 1991 Methods Enzymol 200: 107–111

  • Remy I, Wilson IA and Michnick SW . 1999 Science 283: 990–993

  • Schneider H, Chaovapong W, Matthews D, Karkaria C, Cass RT, Zahn H, Boyle M, Lorenzini T, Elliot SG and Geibel L . 1997 Blood 89: 473–482

  • Seidel HM, Milocco LH, Lamb P, Darnell Jr JE, Stein RB and Rosen J . 1995 Proc Natl Acad Sci USA 92: 3041–3045

  • Shimoda K, van Deursen J, Sangster MY, Sarawar SR, Carson RT, Tripp RA, Chu C, Quelle FW, Nosaka T, Vignali DA, Doherty PC, Grosveld G, Paul WE and Ihle JN . 1996 Nature 380: 630–633

  • Shuai K, Horvath CM, Huang LH, Qureshi SA, Cowburn D and Darnell Jr JE . 1994 Cell 76: 821–828

  • Silverman L, Campbell R and Broach JR . 1998 Curr Opin Chem Biol 2: 397–403

  • Sittampalam GS, Kahl SD and Janzen WP . 1997 Curr Opin Chem Biol 1: 384–391

  • Spielberger RT and Golomb HM . 1992 Leukemia 4: 142–146

  • Starr R, Willson TA, Viney EM, Murray LJ, Rayner JR, Jenkins BJ, Gonda TJ, Alexander WS, Metcalf D, Nicola NA and Hilton DJ . 1997 Nature 387: 917–921

  • Stockwell BR, Haggarty SJ and Schreiber SL . 1999 Chem Biol 6: 71–83

  • Stone WJ, Graber SE, Krantz SB, Dessypris EN, O'Neil VL, Olsen NJ and Pincus TP . 1988 Am J Med Sci 296: 171–179

  • Stryer L . 1978 Annu Rev Biochem 47: 819–846

  • Sudbeck EA, Liu XP, Narla RK, Mahajan S, Ghosh S, Mao C and Uckun FM . 1999 Clin Cancer Res 5: 1569–1582

  • Takeda K, Tanaka T, Shi W, Matsumoto M, Minami M, Kashiwamura S, Nakanishi K, Yoshida N, Kishimoto T and Akira S . 1996 Nature 380: 627–630

  • Targan SR, Hanauer SB, van Deventer SJ, Mayer L, Present DH, Braakman T, DeWoody KL, Schaible TF and Rutgeerts PJ . 1997 N Engl J Med 337: 1029–1035

  • Thierfelder WE, van Deursen JM, Yamamoto K, Tripp RA, Sarawar SR, Carson RT, Sangster MY, Vignali DA, Doherty PC, Grosveld GC and Ihle JN . 1996 Nature 382: 171–174

  • Tian S-S, Lamb P, King AG, Miller SG, Kessler L, Luengo JI, Averill L, Johnson RK, Gleason JG, Pelus LM, Dillon SB and Rosen J . 1998 Science 281: 257–259

  • Trieu VN, Liu R, Liu XP and Uckun FM . 2000 Biochem Biophys Res Commun 267: 22–25

  • Tsui HW, Siminovitch KA, de Souza L and Tsui FW . 1993 Nat Genet 4: 124–129

  • Wagner BJ, Hayes TE, Hoban CJ and Cochran BH . 1990 EMBO J 9: 4477–4484

  • Wang LH, Kirken RA, Erwin RA, Yu CR and Farrar WL . 1999 J Immunol 162: 3897–3904

  • Welte K, Bonilla MA, Gillio AP, Boone TC, Potter GK, Gabrilove JL, Moore MA, O'Reilly RJ and Souza LM . 1987 J Exp Med 165: 941–948

  • Welte K, Gabrilove J, Bronchud MH, Platzer E and Morstyn G . 1996 Blood 88: 1907–1922

  • Whitty A and Borysenko CW . 1999 Chem Biol 6: R107–R118

  • Wu P, Brasseur M and Schindler U . 1997 Anal Biochem 249: 29–36

Download references

Acknowledgements

We thank Peter Syka and Jennifer Haslam for assistance with the STAT biochemical assay and Mechele Cook for help with the manuscript.

Author information

Authors and Affiliations

  1. Ligand Pharmaceuticals, 10275 Science Center Drive, San Diego, 92121, California, CA, USA

    H Martin Seidel, Peter Lamb & Jonathan Rosen

Authors
  1. H Martin Seidel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peter Lamb
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jonathan Rosen
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Seidel, H., Lamb, P. & Rosen, J. Pharmaceutical intervention in the JAK/STAT signaling pathway. Oncogene 19, 2645–2656 (2000). https://doi.org/10.1038/sj.onc.1203550

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1203550

Keywords

This article is cited by

Search

Advanced search

Quick links