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Small Molecules That Inhibit Notch Signaling

  • Gerdien E. De Kloe
  • Bart De StrooperEmail author
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 1187)

Abstract

The proteolytic processing of Notch receptors plays a central role in the transduction of Notch signaling, which is involved in a variety of important processes in the body. Abnormal Notch processing has been implicated in a variety of cancers. γ-Secretase is responsible for the third and last cleavage step of Notch receptors. Since γ-secretase plays an important role in Alzheimer’s disease, great effort has been spent to develop γ-secretase inhibitors (GSIs). The majority of these inhibitors block γ-secretase nonselectively, which means that these compounds can be used to block Notch cleavage and thereby regulate Notch signaling. In this review we give an overview of the most-used GSIs in the Notch field, together with examples of their use. It is a huge advantage that these drug-like compounds are already optimized for γ-secretase, and some are already being used in clinical trials. However, their nonspecificity has disadvantages as well, since four Notch receptors exist with different sites of expression and different roles in cell signaling and at least four different γ-secretase proteases are involved in their cleavage. It would be worth the effort to screen many GSIs for their selectivity for the different Notch receptors and γ-secretases, in order to obtain interesting tools for further research and—in the end—to develop safer drugs.

Key words

Notch γ-secretase inhibitors Transition-state analogs Allosteric inhibitors Selectivity 

Notes

Acknowledgements

This work was supported by VIB, a Methusalem grant from KU Leuven and the Flemish government, Janssen Pharmaceutica, and the Arthur Bax and Anna Van Luffelen foundation.

References

  1. 1.
    Kopan R, Ilagan MX (2009) The canonical Notch signaling pathway: unfolding the activation mechanism. Cell 137:216–233PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Hartmann D, de Strooper B, Serneels L et al (2002) The disintegrin/metalloprotease ADAM 10 is essential for Notch signalling but not for alpha-secretase activity in fibroblasts. Hum Mol Genet 11:2615–2624PubMedCrossRefGoogle Scholar
  3. 3.
    De Strooper B, Annaert W, Cupers P et al (1999) A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature 398:518–522PubMedCrossRefGoogle Scholar
  4. 4.
    Struhl G, Greenwald I (1999) Presenilin is required for activity and nuclear access of Notch in Drosophila. Nature 398:522–555PubMedCrossRefGoogle Scholar
  5. 5.
    De Strooper B (2003) Aph-1, Pen-2, and Nicastrin with Presenilin generate an active gamma-Secretase complex. Neuron 38:9–12PubMedCrossRefGoogle Scholar
  6. 6.
    De Strooper B, Vassar R, Golde T (2010) The secretases: enzymes with therapeutic potential in Alzheimer disease. Nat Rev Neurol 6:99–107PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Doody RS, Raman R, Farlow M et al (2013) A phase 3 trial of semagacestat for treatment of Alzheimer’s disease. N Engl J Med 369:341–350PubMedCrossRefGoogle Scholar
  8. 8.
    Wolfe MS, Xia W, Ostaszewski BL et al (1999) Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity. Nature 398:513–517PubMedCrossRefGoogle Scholar
  9. 9.
    Serneels L, Van Biervliet J, Craessaerts K et al (2009) gamma-Secretase heterogeneity in the Aph1 subunit: relevance for Alzheimer’s disease. Science 324:639–642PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Levitan D, Greenwald I (1995) Facilitation of lin-12-mediated signalling by sel-12, a Caenorhabditis elegans S182 Alzheimer’s disease gene. Nature 377:351–354PubMedCrossRefGoogle Scholar
  11. 11.
    Shen J, Bronson RT, Chen DF et al (1997) Skeletal and CNS defects in Presenilin-1-deficient mice. Cell 89:629–639PubMedCrossRefGoogle Scholar
  12. 12.
    Wong PC, Zheng H, Chen H et al (1997) Presenilin 1 is required for Notch 1 and Dll1 expression in the paraxial mesoderm. Nature 387:288–292PubMedCrossRefGoogle Scholar
  13. 13.
    Geling A, Steiner H, Willem M et al (2002) A gamma-secretase inhibitor blocks Notch signaling in vivo and causes a severe neurogenic phenotype in zebrafish. EMBO Rep 3:688–694PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Lewis HD, Pérez Revuelta BI, Nadin A et al (2003) Catalytic site-directed gamma-secretase complex inhibitors do not discriminate pharmacologically between Notch S3 and beta-APP cleavages. Biochemistry 42:7580–7586PubMedCrossRefGoogle Scholar
  15. 15.
    van Es JH, Clevers H (2005) Notch and Wnt inhibitors as potential new drugs for intestinal neoplastic disease. Trends Mol Med 11:496–502PubMedCrossRefGoogle Scholar
  16. 16.
    Wong GT, Manfra D, Poulet FM et al (2004) Chronic treatment with the gamma-secretase inhibitor LY-411,575 inhibits beta-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation. J Biol Chem 279:12876–12882PubMedCrossRefGoogle Scholar
  17. 17.
    Demehri S, Turkoz A, Kopan R (2009) Epidermal Notch1 loss promotes skin tumorigenesis by impacting the stromal microenvironment. Cancer Cell 16:55–66PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Groth C, Fortini ME (2012) Therapeutic approaches to modulating Notch signaling: current challenges and future prospects. Semin Cell Dev Biol 23:465–472PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Li YM, Xu M, Lai MT et al (2000) Photoactivated gamma-secretase inhibitors directed to the active site covalently label presenilin 1. Nature 405:689–694PubMedCrossRefGoogle Scholar
  20. 20.
    Kreft AF, Martone R, Porte A (2009) Recent advances in the identification of gamma-secretase inhibitors to clinically test the Abeta oligomer hypothesis of Alzheimer’s disease. J Med Chem 52:6169–6188PubMedCrossRefGoogle Scholar
  21. 21.
    Das C, Berezovska O, Diehl TS et al (2003) Designed helical peptides inhibit an intramembrane protease. J Am Chem Soc 125:11794–11795PubMedCrossRefGoogle Scholar
  22. 22.
    Bihel F, Das C, Bowman MJ et al (2004) Discovery of a subnanomolar helical D-tridecapeptide inhibitor of gamma-secretase. J Med Chem 47:3931–3933PubMedCrossRefGoogle Scholar
  23. 23.
    Dovey HF, John V, Anderson JP et al (2001) Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain. J Neurochem 76:173–181PubMedCrossRefGoogle Scholar
  24. 24.
    McKee TD, Loureiro RM, Dumin JA et al (2013) An improved cell-based method for determining the γ-secretase enzyme activity against both Notch and APP substrates. J Neurosci Methods 213:14–21PubMedCrossRefGoogle Scholar
  25. 25.
    Borgegård T, Gustavsson S, Nilsson C et al (2012) Alzheimer’s disease: presenilin 2-sparing γ-Secretase inhibition is a tolerable Aβ peptide-lowering strategy. J Neurosci 32:17297–17305PubMedCrossRefGoogle Scholar
  26. 26.
    Churcher I, Ashton K, Butcher JW et al (2003) A new series of potent benzodiazepine gamma-secretase inhibitors. Bioorg Med Chem Lett 13:179–183PubMedCrossRefGoogle Scholar
  27. 27.
    Churcher I, Williams S, Kerrad S et al (2003) Design and synthesis of highly potent benzodiazepine gamma-secretase inhibitors: preparation of (2S,3R)-3-(3,4-difluorophenyl)-2-(4-fluorophenyl)-4- hydroxy-N-((3S)-1-methyl-2-oxo-5- phenyl-2,3-dihydro-1H-benzo[e][1,4]-diazepin-3-yl)butyramide by use of an asymmetric Ireland-Claisen rearrangement. J Med Chem 46:2275–2278PubMedCrossRefGoogle Scholar
  28. 28.
    Yang MG, Shi JL, Modi DP et al (2007) Design and synthesis of benzoazepinone-derived cyclic malonamides and aminoamides as potent gamma-secretase inhibitors. Bioorg Med Chem Lett 17:3910–3915PubMedCrossRefGoogle Scholar
  29. 29.
    Quesnelle C, Kim S-H, Lee F, et al. (2012) Bisfluoroalkyl-1,4-benzodiazepinone compounds WO/2012/129353Google Scholar
  30. 30.
  31. 31.
  32. 32.
    Wei P, Walls M, Qiu M et al (2010) Evaluation of selective γ-secretase inhibitor PF-03084014 for its antitumor efficacy and gastrointestinal safety to guide optimal clinical trial design. Mol Cancer Ther 9:1618–1628PubMedCrossRefGoogle Scholar
  33. 33.
    Zhang CC, Yan Z, Zong Q et al (2013) Synergistic effect of the γ-secretase inhibitor PF-03084014 and docetaxel in breast cancer models. Stem Cells Transl Med 2:233–242PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Mayer SC, Kreft AF, Harrison B et al (2008) Discovery of begacestat, a Notch-1-sparing gamma-secretase inhibitor for the treatment of Alzheimer’s disease. J Med Chem 51:7348–7351PubMedCrossRefGoogle Scholar
  35. 35.
    Krop I, Demuth T, Guthrie T et al (2012) Phase I pharmacologic and pharmacodynamic study of the gamma secretase (Notch) inhibitor MK-0752 in adult patients with advanced solid tumors. J Clin Oncol 30:2307–2313PubMedCrossRefGoogle Scholar
  36. 36.
    Chen SM, Liu JP, Zhou JX et al (2011) Suppression of the notch signaling pathway by gamma-secretase inhibitor GSI inhibits human nasopharyngeal carcinoma cell proliferation. Cancer Lett 306:76–84PubMedCrossRefGoogle Scholar
  37. 37.
    Shi W, Harris AL (2006) Notch signaling in breast cancer and tumor angiogenesis: cross-talk and therapeutic potentials. J Mammary Gland Biol Neoplasia 11:41–52PubMedCrossRefGoogle Scholar
  38. 38.
    Tran IT, Sandy AR, Carulli AJ et al (2013) Blockade of individual Notch ligands and receptors controls graft-versus-host disease. J Clin Invest 123:1590–1604PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Shen Y, Lv D, Wang J et al (2012) GSI-I has a better effect in inhibiting hepatocellular carcinoma cell growth than GSI-IX, GSI-X, or GSI-XXI. Anticancer Drugs 23:683–690PubMedCrossRefGoogle Scholar
  40. 40.
    Groth C, Alvord WG, Quiñones OA et al (2010) Pharmacological analysis of Drosophila melanogaster gamma-secretase with respect to differential proteolysis of Notch and APP. Mol Pharmacol 77:567–574PubMedCentralPubMedCrossRefGoogle Scholar
  41. 41.
    Kamstrup MR, Biskup E, Gniadecki R (2010) Notch signalling in primary cutaneous CD30+ lymphoproliferative disorders: a new therapeutic approach? Br J Dermatol 163:781–788PubMedCrossRefGoogle Scholar
  42. 42.
    Gu W, Xu W, Ding T et al (2012) Fringe controls naive CD4(+)T cells differentiation through modulating notch signaling in asthmatic rat models. PLoS One 7:e47288PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Harrison H, Simões BM, Rogerson L et al (2013) Oestrogen increases the activity of oestrogen receptor negative breast cancer stem cells through paracrine EGFR and Notch signalling. Breast Cancer Res 15:R21PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Wang SF, Aoki M, Nakashima Y et al (2008) Development of Notch-dependent T-cell leukemia by deregulated Rap1 signaling. Blood 111:2878–2886PubMedCrossRefGoogle Scholar
  45. 45.
    Pancewicz J, Taylor JM, Datta A et al (2010) Notch signaling contributes to proliferation and tumor formation of human T-cell leukemia virus type 1-associated adult T-cell leukemia. Proc Natl Acad Sci U S A 107:16619–16624PubMedCentralPubMedCrossRefGoogle Scholar
  46. 46.
    Sainson RC, Aoto J, Nakatsu MN et al (2005) Cell-autonomous notch signaling regulates endothelial cell branching and proliferation during vascular tubulogenesis. FASEB J 19:1027–1029PubMedGoogle Scholar
  47. 47.
    Ota H, Katsube K, Ogawa J et al (2007) Hypoxia/Notch signaling in primary culture of rat lymphatic endothelial cells. FEBS Lett 581:5220–5226PubMedCrossRefGoogle Scholar
  48. 48.
    Nwabo Kamdje AH, Bassi G, Pacelli L et al (2012) Role of stromal cell-mediated Notch signaling in CLL resistance to chemotherapy. Blood Cancer J 2:e73PubMedCrossRefGoogle Scholar
  49. 49.
    Joshi I, Minter LM, Telfer J et al (2009) Notch signaling mediates G1/S cell-cycle progression in T cells via cyclin D3 and its dependent kinases. Blood 113:1689–1698PubMedCentralPubMedCrossRefGoogle Scholar
  50. 50.
    van Es JH, van Gijn ME, Riccio O et al (2005) Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature 435:959–963PubMedCrossRefGoogle Scholar
  51. 51.
    van Es JH, de Geest N, van de Born M et al (2010) Intestinal stem cells lacking the Math1 tumour suppressor are refractory to Notch inhibitors. Nat Commun 1:18PubMedGoogle Scholar
  52. 52.
    Okamoto M, Matsuda H, Joetham A et al (2009) Jagged1 on dendritic cells and Notch on CD4+ T cells initiate lung allergic responsiveness by inducing IL-4 production. J Immunol 183:2995–3003PubMedCrossRefGoogle Scholar
  53. 53.
    Liu S, Breit S, Danckwardt S et al (2009) Downregulation of Notch signaling by gamma-secretase inhibition can abrogate chemotherapy-induced apoptosis in T-ALL cell lines. Ann Hematol 88:613–621PubMedCrossRefGoogle Scholar
  54. 54.
    Gusscott S, Kuchenbauer F, Humphries RK et al (2012) Notch-mediated repression of miR-223 contributes to IGF1R regulation in T-ALL. Leuk Res 36:905–911PubMedCrossRefGoogle Scholar
  55. 55.
    Mizutari K, Fujioka M, Hosoya M et al (2013) Notch inhibition induces cochlear hair cell regeneration and recovery of hearing after acoustic trauma. Neuron 77:58–69PubMedCentralPubMedCrossRefGoogle Scholar
  56. 56.
    Curry CL, Reed LL, Golde TE et al (2005) Gamma secretase inhibitor blocks Notch activation and induces apoptosis in Kaposi’s sarcoma tumor cells. Oncogene 24:6333–6344PubMedGoogle Scholar
  57. 57.
    Pandya K, Meeke K, Clementz AG et al (2011) Targeting both Notch and ErbB-2 signalling pathways is required for prevention of ErbB-2-positive breast tumour recurrence. Br J Cancer 105:796–806PubMedCentralPubMedCrossRefGoogle Scholar
  58. 58.
    Okamoto R, Tsuchiya K, Nemoto Y et al (2009) Requirement of Notch activation during regeneration of the intestinal epithelia. Am J Physiol Gastrointest Liver Physiol 296:G23–G35PubMedCrossRefGoogle Scholar
  59. 59.
    Luistro L, He W, Smith M et al (2009) Preclinical profile of a potent gamma-secretase inhibitor targeting notch signaling with in vivo efficacy and pharmacodynamic properties. Cancer Res 69:7672–7680PubMedCrossRefGoogle Scholar
  60. 60.
    Debeb BG, Cohen EN, Boley K et al (2012) Pre-clinical studies of Notch signaling inhibitor RO4929097 in inflammatory breast cancer cells. Breast Cancer Res Treat 134:495–510PubMedCrossRefGoogle Scholar
  61. 61.
    Huynh C, Poliseno L, Segura MF et al (2011) The novel gamma secretase inhibitor RO4929097 reduces the tumor initiating potential of melanoma. PLoS One 6:e25264PubMedCentralPubMedCrossRefGoogle Scholar
  62. 62.
    Osanyingbemi-Obidi J, Dobromilskaya I, Illei PB et al (2011) Notch signaling contributes to lung cancer clonogenic capacity in vitro but may be circumvented in tumorigenesis in vivo. Mol Cancer Res 9:1746–1754PubMedCentralPubMedCrossRefGoogle Scholar
  63. 63.
    Sethi N, Dai X, Winter CG et al (2011) Tumor-derived JAGGED1 promotes osteolytic bone metastasis of breast cancer by engaging notch signaling in bone cells. Cancer Cell 19:192–205PubMedCentralPubMedCrossRefGoogle Scholar
  64. 64.
    Real PJ, Ferrando AA (2009) NOTCH inhibition and glucocorticoid therapy in T-cell acute lymphoblastic leukemia. Leukemia 23:1374–1377PubMedCentralPubMedCrossRefGoogle Scholar
  65. 65.
    DeAngelo DJ, Stone RM, Silverman LB (2006) A phase I clinical trial of the notch inhibitor MK-0752 in patients with T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) and other leukemias. J Clin Oncol 24(18S):6585Google Scholar
  66. 66.
    Real PJ, Tosello V, Palomero T et al (2009) Gamma-secretase inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia. Nat Med 15:50–58PubMedCentralPubMedCrossRefGoogle Scholar
  67. 67.
    Konishi J, Kawaguchi KS, Vo H et al (2007) Gamma-secretase inhibitor prevents Notch3 activation and reduces proliferation in human lung cancers. Cancer Res 67:8051–8057PubMedCrossRefGoogle Scholar
  68. 68.
    Purow B (2012) Notch inhibition as a promising new approach to cancer therapy. Adv Exp Med Biol 727:305–319PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.VIB Center for the Biology of DiseaseLeuvenBelgium
  2. 2.VIB Center for the Biology of Disease and Center for Human Genetics and Institute of Neuroscience & Disease (LIND)KU Leuven and universitaire ziekenhuizenLeuvenBelgium

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