γ-Secretase inhibitors and modulators

Biochimica et Biophysica Acta - Biomembranes

Volumn 1828, Issue 12, 2013, Pages 2898-2907

  Golde, Todd E ^a   Koo, Edward H ^b   Felsenstein, Kevin M ^a   Osborne, Barbara A ^c   Miele, Lucio ^d  

^a UNIVERSITY OF FLORIDA COLLEGE OF MEDICINE   (United States)

^b UNIVERSITY OF CALIFORNIA   (United States)

^c UNIVERSITY OF MASSACHUSETTS   (United States)

^d UNIVERSITY OF MISSISSIPPI SCHOOL OF MEDICINE   (United States)

Author keywords

Secretase inhibitor; Secretase modulator; Alzheimer's disease; Cancer

Indexed keywords

AGENTS AFFECTING WATER, MOLECULE OR ION TRANSPORT; AMYLOID BETA PROTEIN; AMYLOID BETA PROTEIN[1-40]; AMYLOID BETA PROTEIN[1-42]; ANTERIOR PHARYNX DEFECTIVE 1 PROTEIN; AVAGACESTAT; BEGACESTAT; CHF 5074; E 2012; ELN 475516; GAMMA SECRETASE; GAMMA SECRETASE INHIBITOR; GAMMA SECRETASE MODULATOR; GSM 1; INDOMETACIN; MK 0752; MRK 003; N (6,7 DIHYDRO 6 OXO 5H DIBENZ[B,D]AZEPIN 7 YL) 2,2 DIMETHYL N' (2,2,3,3,3 PENTAFLUOROPROPYL)PROPANEDIAMIDE; N2 [2 (3,5 DIFLUOROPHENYL) 2 HYDROXYACETYL] N1 (6,7 DIHYDRO 5 METHYL 6 OXO 5H DIBENZ[B,D]AZEPIN 7 YL)ALANINAMIDE; NICASTRIN; NOTCH1 RECEPTOR; PF 3084014; PRESENILIN 1; PRESENILIN 2; SEMAGACESTAT; TARENFLURBIL; UNCLASSIFIED DRUG; AMYLOID PRECURSOR PROTEIN; PROTEIN BINDING; PROTEIN SUBUNIT; PROTEINASE INHIBITOR; SECRETASE;

ALZHEIMER DISEASE; BREAST CANCER; COLORECTAL CANCER; DRUG EFFICACY; DRUG INDICATION; DRUG MECHANISM; DRUG SAFETY; DRUG SCREENING; DRUG STRUCTURE; DRUG TARGETING; ENDOMETRIUM CANCER; ENZYME INHIBITION; ENZYME SUBSTRATE; GLIOBLASTOMA; GLIOMA; HUMAN; KIDNEY CANCER; LEUKEMIA; LUNG CANCER; LYMPHOMA; MALIGNANT NEOPLASTIC DISEASE; MELANOMA; NONHUMAN; OVARY CANCER; PANCREAS CANCER; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; PROSTATE CANCER; PROTEIN CLEAVAGE; REVIEW; RISK BENEFIT ANALYSIS; SARCOMA; SIGNAL TRANSDUCTION; ANTAGONISTS AND INHIBITORS; BINDING SITE; CHEMISTRY; CLINICAL TRIAL (TOPIC); DRUG DESIGN; ENZYME SPECIFICITY; ENZYMOLOGY; METABOLISM; NEOPLASMS; PATHOLOGY; PROTEIN DEGRADATION; PROTEIN SUBUNIT; STRUCTURE ACTIVITY RELATION;

ALZHEIMER DISEASE; AMYLOID BETA-PROTEIN PRECURSOR; AMYLOID PRECURSOR PROTEIN SECRETASES; BINDING SITES; CLINICAL TRIALS AS TOPIC; DRUG DESIGN; HUMANS; NEOPLASMS; PROTEASE INHIBITORS; PROTEIN BINDING; PROTEIN SUBUNITS; PROTEOLYSIS; SIGNAL TRANSDUCTION; STRUCTURE-ACTIVITY RELATIONSHIP; SUBSTRATE SPECIFICITY;

EID: 84885172858     PISSN: 00052736     EISSN: 18792642     Source Type: Journal    
DOI: 10.1016/j.bbamem.2013.06.005     Document Type: Review

References (194)

1. N. Takasugi, T. Tomita, I. Hayashi, M. Tsuruoka, M. Niimura, Y. Takahashi, G. Thinakaran, and T. Iwatsubo The role of presenilin cofactors in the gamma-secretase complex Nature 422 2003 438 441 (Pubitemid 36411397)
2. B. De Strooper Aph-1, Pen-2, and Nicastrin with Presenilin generate an active gamma-secretase complex Neuron 38 2003 9 12 (Pubitemid 36423348)
3. M.S. Wolfe, and R. Kopan Intramembrane proteolysis: theme and variations Science 305 2004 1119 1123 (Pubitemid 39100316)
4. A. Haapasalo, and D.M. Kovacs The many substrates of presenilin/gamma- secretase J. Alzheimers Dis. 25 1 2011 3 28
5. M. Shoji, T.E. Golde, J. Ghiso, T.T. Cheung, S. Estus, L.M. Shaffer, X.D. Cai, D.M. McKay, R. Tintner, and B. Frangione Production of the Alzheimer amyloid beta protein by normal proteolytic processing Science 258 1992 126 129
6. C. Haass, M.G. Schlossmacher, A.Y. Hung, C. Vigo-Pelfrey, A. Mellon, B.L. Ostaszewski, I. Lieberburg, E.H. Koo, D. Schenk, and D.B. Teplow Amyloid beta-peptide is produced by cultured cells during normal metabolism [see comments] Nature 359 1992 322 325
7. E.H. Schroeter, J.A. Kisslinger, and R. Kopan Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain [see comments] Nature 393 1998 382 386 (Pubitemid 28269713)
8. B. De Strooper, W. Annaert, P. Cupers, P. Saftig, K. Craessaerts, J.S. Mumm, E.H. Schroeter, V. Schrijvers, M.S. Wolfe, W.J. Ray, A. Goate, and R. Kopan A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain Nature 398 1999 518 522
9. R. Kopan, and M.X. Ilagan Gamma-secretase: proteasome of the membrane? Nat. Rev. Mol. Cell Biol. 5 2004 499 504
10. T.E. Golde, and C.B. Eckman Physiologic and pathologic events mediated by intramembranous and juxtamembranous proteolysis Sci. STKE 2003 2003 RE4
11. B. De Strooper, R. Vassar, and T. Golde The secretases: enzymes with therapeutic potential in Alzheimer disease Nat. Rev. Neurol. 6 2010 99 107
12. K.S. Vetrivel, H. Cheng, S.H. Kim, Y. Chen, N.Y. Barnes, A.T. Parent, S.S. Sisodia, and G. Thinakaran Spatial segregation of gamma-secretase and substrates in distinct membrane domains J. Biol. Chem. 280 2005 25892 25900 (Pubitemid 40962301)
13. Y. Gu, H. Misonou, T. Sato, N. Dohmae, K. Takio, and Y. Ihara Distinct intramembrane cleavage of the beta-amyloid precursor protein family resembling gamma-secretase-like cleavage of Notch J. Biol. Chem. 276 2001 35235 35238
14. M. Takami, Y. Nagashima, Y. Sano, S. Ishihara, M. Morishima-Kawashima, S. Funamoto, and Y. Ihara gamma-Secretase: successive tripeptide and tetrapeptide release from the transmembrane domain of beta-carboxyl terminal fragment J. Neurosci. 29 2009 13042 13052
15. I. Pinnix, U. Musunuru, H. Tun, A. Sridharan, T. Golde, C. Eckman, C. Ziani-Cherif, L. Onstead, and K. Sambamurti A novel gamma-secretase assay based on detection of the putative C-terminal fragment-gamma of amyloid beta protein precursor J. Biol. Chem. 276 2001 481 487 (Pubitemid 32050342)
16. T.E. Golde, L. Petrucelli, and J. Lewis Targeting Abeta and tau in Alzheimer's disease, an early interim report Exp. Neurol. 223 2010 252 266
17. M.S. Wolfe Inhibition and modulation of gamma-secretase for Alzheimer's disease Neurotherapeutics 5 2008 391 398 (Pubitemid 351952492)
18. R.J. Bateman, E.R. Siemers, K.G. Mawuenyega, G. Wen, K.R. Browning, W.C. Sigurdson, K.E. Yarasheski, S.W. Friedrich, R.B. Demattos, P.C. May, S.M. Paul, and D.M. Holtzman A gamma-secretase inhibitor decreases amyloid-beta production in the central nervous system Ann. Neurol. 66 2009 48 54
19. E.R. Siemers, R.A. Dean, S. Friedrich, L. Ferguson-Sells, C. Gonzales, M.R. Farlow, and P.C. May Safety, tolerability, and effects on plasma and cerebrospinal fluid amyloid-beta after inhibition of gamma-secretase Clin. Neuropharmacol. 30 2007 317 325 (Pubitemid 350307310)
20. H.F. Dovey, V. John, J.P. Anderson, L.Z. Chen, P. de Saint Andrieu, L.Y. Fang, S.B. Freedman, B. Folmer, E. Goldbach, E.J. Holsztynska, K.L. Hu, K.L. Johnson-Wood, S.L. Kennedy, D. Kholodenko, J.E. Knops, L.H. Latimer, M. Lee, Z. Liao, I.M. Lieberburg, R.N. Motter, L.C. Mutter, J. Nietz, K.P. Quinn, K.L. Sacchi, P.A. Seubert, G.M. Shopp, E.D. Thorsett, J.S. Tung, J. Wu, S. Yang, C.T. Yin, D.B. Schenk, P.C. May, L.D. Altstiel, M.H. Bender, L.N. Boggs, T.C. Britton, J.C. Clemens, D.L. Czilli, D.K. Dieckman-McGinty, J.J. Droste, K.S. Fuson, B.D. Gitter, P.A. Hyslop, E.M. Johnstone, W.Y. Li, S.P. Little, T.E. Mabry, F.D. Miller, and J.E. Audia Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain J. Neurochem. 76 2001 173 181 (Pubitemid 32044380)
21. D. Abramowski, K.H. Wiederhold, U. Furrer, A.L. Jaton, A. Neuenschwander, M.J. Runser, S. Danner, J. Reichwald, D. Ammaturo, D. Staab, M. Stoeckli, H. Rueeger, U. Neumann, and M. Staufenbiel Dynamics of Abeta turnover and deposition in different beta-amyloid precursor protein transgenic mouse models following gamma-secretase inhibition J. Pharmacol. Exp. Ther. 327 2008 411 424
22. D. Seiffert, J.D. Bradley, C.M. Rominger, D.H. Rominger, F. Yang, J.E. Meredith Jr., Q. Wang, A.H. Roach, L.A. Thompson, S.M. Spitz, J.N. Higaki, S.R. Prakash, A.P. Combs, R.A. Copeland, S.P. Arneric, P.R. Hartig, D.W. Robertson, B. Cordell, A.M. Stern, R.E. Olson, and R. Zaczek Presenilin-1 and -2 are molecular targets for gamma-secretase inhibitors [in process citation] J. Biol. Chem. 275 2000 34086 34091
23. J.N. Higaki, S. Chakravarty, C.M. Bryant, L.R. Cowart, P. Harden, J.M. Scardina, B. Mavunkel, G.R. Luedtke, and B. Cordell A combinatorial approach to the identification of dipeptide aldehyde inhibitors of beta-amyloid production J. Med. Chem. 42 1999 3889 3898 (Pubitemid 29453469)
24. J. Higaki, G.M. Murphy, and B. Cordell Inhibition of beta-amyloid formation by haloperidol - a possible mechanism for reduced frequency of Alzheimer's disease pathology in schizophrenia J. Neurochem. 68 1997 333 336 (Pubitemid 26427325)
25. Y.M. Li, M. Xu, M.T. Lai, Q. Huang, J.L. Castro, J. DiMuzio-Mower, T. Harrison, C. Lellis, A. Nadin, J.G. Neduvelil, R.B. Register, M.K. Sardana, M.S. Shearman, A.L. Smith, X.P. Shi, K.C. Yin, J.A. Shafer, and S.J. Gardell Photoactivated gamma-secretase inhibitors directed to the active site covalently label presenilin 1 [in process citation] Nature 405 2000 689 694 (Pubitemid 30428655)
26. Y.M. Li, M.T. Lai, M. Xu, Q. Huang, J. DiMuzio-Mower, M.K. Sardana, X.P. Shi, K.C. Yin, J.A. Shafer, and S.J. Gardell Presenilin 1 is linked with gamma-secretase activity in the detergent solubilized state Proc. Natl. Acad. Sci. U. S. A. 97 2000 6138 6143 (Pubitemid 30367536)
27. M.S. Wolfe, M. Citron, T.S. Diehl, W. Xia, I.O. Donkor, and D.J. Selkoe A substrate-based difluoro ketone selectively inhibits Alzheimer's gamma-secretase activity J. Med. Chem. 41 1998 6 9
28. C.V. Prasad, S. Vig, D.W. Smith, Q. Gao, C.T. Polson, J.A. Corsa, V.L. Guss, A. Loo, D.M. Barten, M. Zheng, K.M. Felsenstein, and S.B. Roberts 2,3-Benzodiazepin-1,4-diones as peptidomimetic inhibitors of gamma-secretase Bioorg. Med. Chem. Lett. 14 2004 3535 3538
29. D.M. Barten, V.L. Guss, J.A. Corsa, A. Loo, S.B. Hansel, M. Zheng, B. Munoz, K. Srinivasan, B. Wang, B.J. Robertson, C.T. Polson, J. Wang, S.B. Roberts, J.P. Hendrick, J.J. Anderson, J.K. Loy, R. Denton, T.A. Verdoorn, D.W. Smith, and K.M. Felsenstein Dynamics of {beta}-amyloid reductions in brain, cerebrospinal fluid, and plasma of {beta}-amyloid precursor protein transgenic mice treated with a {gamma}-secretase inhibitor J. Pharmacol. Exp. Ther. 312 2005 635 643 (Pubitemid 40189561)
30. M.P. Murphy, S.N. Uljon, P.E. Fraser, A. Fauq, H.A. Lookingbill, K.A. Findlay, T.E. Smith, P.A. Lewis, D.C. McLendon, R. Wang, and T.E. Golde Presenilin 1 regulates pharmacologically distinct gamma-secretase activities. Implications for the role of presenilin in gamma-secretase cleavage J. Biol. Chem. 275 2000 26277 26284
31. M.P. Murphy, R. Wang, P.E. Fraser, A. Fauq, and T.E. Golde An empirical model of gamma-secretase activity Ann. N. Y. Acad. Sci. 920 2000 233 240
32. M.P. Murphy, L.J. Hickman, C.B. Eckman, S.N. Uljon, R. Wang, and T.E. Golde Gamma-secretase, evidence for multiple proteolytic activities and influence of membrane positioning of substrate on generation of amyloid beta peptides of varying length J. Biol. Chem. 274 1999 11914 11923
33. M. Citron, T.S. Diehl, G. Gordon, A.L. Biere, P. Seubert, and D.J. Selkoe Evidence that the 42- and 40-amino acid forms of amyloid beta protein are generated from the beta-amyloid precursor protein by different protease activities Proc. Natl. Acad. Sci. U. S. A. 93 1996 13170 13175 (Pubitemid 26382788)
34. M.S. Wolfe, W.M. Xia, B.L. Ostaszewski, T.S. Diehl, W.T. Kimberly, and D.J. Selkoe Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity Nature 398 1999 513 517
35. A. Weihofen, K. Binns, M.K. Lemberg, K. Ashman, and B. Martoglio Identification of signal peptide peptidase, a presenilin-type aspartic protease Science 296 2002 2215 2218 (Pubitemid 34680305)
36. B. Martoglio, and T.E. Golde Intramembrane-cleaving aspartic proteases and disease: presenilins, signal peptide peptidase and their homologs Hum. Mol. Genet. 12 2003 R201 R206 (Spec No 2)
37. C.P. Ponting, M. Hutton, A. Nyborg, M. Baker, K. Jansen, and T.E. Golde Identification of a novel family of presenilin homologues Hum. Mol. Genet. 11 2002 1037 1044 (Pubitemid 34521085)
38. A.C. Nyborg, K. Jansen, T.B. Ladd, A. Fauq, and T.E. Golde A signal peptide peptidase (SPP) reporter activity assay based on the cleavage of type II membrane protein substrates provides further evidence for an inverted orientation of the SPP active site relative to presenilin J. Biol. Chem. 279 2004 43148 43156 (Pubitemid 39372210)
39. A.C. Nyborg, A.Y. Kornilova, K. Jansen, T.B. Ladd, M.S. Wolfe, and T.E. Golde Signal peptide peptidase forms a homodimer that is labeled by an active site-directed gamma-secretase inhibitor J. Biol. Chem. 279 2004 15153 15160 (Pubitemid 38618910)
40. X. Li, S. Dang, C. Yan, X. Gong, J. Wang, and Y. Shi Structure of a presenilin family intramembrane aspartate protease Nature 493 2013 56 61
41. R. Fluhrer, G. Grammer, L. Israel, M.M. Condron, C. Haffner, E. Friedmann, C. Bohland, A. Imhof, B. Martoglio, D.B. Teplow, and C. Haass A gamma-secretase-like intramembrane cleavage of TNFalpha by the GxGD aspartyl protease SPPL2b Nat. Cell Biol. 8 2006 894 896 (Pubitemid 44151595)
42. L.G. Iben, R.E. Olson, L.A. Balanda, S. Jayachandra, B.J. Robertson, V. Hay, J. Corradi, C.V. Prasad, R. Zaczek, C.F. Albright, and J.H. Toyn Signal peptide peptidase and gamma-secretase share equivalent inhibitor binding pharmacology J. Biol. Chem. 282 2007 36829 36836
43. M.B. Harbut, B.A. Patel, B.K. Yeung, C.W. McNamara, A.T. Bright, J. Ballard, F. Supek, T.E. Golde, E.A. Winzeler, T.T. Diagana, and D.C. Greenbaum Targeting the ERAD pathway via inhibition of signal peptide peptidase for antiparasitic therapeutic design Proc. Natl. Acad. Sci. U. S. A. 109 2012 21486 21491
44. I. Parvanova, S. Epiphanio, A. Fauq, T.E. Golde, M. Prudencio, and M.M. Mota A small molecule inhibitor of signal peptide peptidase inhibits Plasmodium development in the liver and decreases malaria severity PLoS One 4 2009 e5078
45. P. Targett-Adams, T. Schaller, G. Hope, R.E. Lanford, S.M. Lemon, A. Martin, and J. McLauchlan Signal peptide peptidase cleavage of GB virus B core protein is required for productive infection in vivo J. Biol. Chem. 281 2006 29221 29227 (Pubitemid 44507065)
46. A.L. Bronckers, N. Guneli, R. Lullmann-Rauch, J. Schneppenheim, A.P. Moraru, N. Himmerkus, T.J. Bervoets, R. Fluhrer, V. Everts, P. Saftig, and B. Schroder The intramembrane protease SPPL2A is critical for tooth enamel formation J. Bone Miner. Res. 28 7 2013 1622 1630
47. H. Bergmann, M. Yabas, A. Short, L. Miosge, N. Barthel, C.E. Teh, C.M. Roots, K.R. Bull, Y. Jeelall, K. Horikawa, B. Whittle, B. Balakishnan, G. Sjollema, E.M. Bertram, F. Mackay, A.J. Rimmer, R.J. Cornall, M.A. Field, T.D. Andrews, C.C. Goodnow, and A. Enders B cell survival, surface BCR and BAFFR expression, CD74 metabolism, and CD8-dendritic cells require the intramembrane endopeptidase SPPL2A J. Exp. Med. 210 2013 31 40
48. J. Schneppenheim, R. Dressel, S. Huttl, R. Lullmann-Rauch, M. Engelke, K. Dittmann, J. Wienands, E.L. Eskelinen, I. Hermans-Borgmeyer, R. Fluhrer, P. Saftig, and B. Schroder The intramembrane protease SPPL2a promotes B cell development and controls endosomal traffic by cleavage of the invariant chain J. Exp. Med. 210 2013 41 58
49. D.R. Beisner, P. Langerak, A.E. Parker, C. Dahlberg, F.J. Otero, S.E. Sutton, L. Poirot, W. Barnes, M.A. Young, S. Niessen, T. Wiltshire, U. Bodendorf, B. Martoglio, B. Cravatt, and M.P. Cooke The intramembrane protease Sppl2a is required for B cell and DC development and survival via cleavage of the invariant chain J. Exp. Med. 210 2013 23 30
50. M. Voss, A. Fukumori, P.H. Kuhn, U. Kunzel, B. Klier, G. Grammer, M. Haug-Kroper, E. Kremmer, S.F. Lichtenthaler, H. Steiner, B. Schroder, C. Haass, and R. Fluhrer Foamy virus envelope protein is a substrate for signal peptide peptidase-like 3 (SPPL3) J. Biol. Chem. 287 2012 43401 43409
51. J. Hardy, and D.J. Selkoe The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics Science 297 2002 353 356 (Pubitemid 34790756)
52. T.E. Golde, L.S. Schneider, and E.H. Koo Anti-Abeta therapeutics in Alzheimer's disease: the need for a paradigm shift Neuron 69 2011 203 213
53. P. Das, C. Verbeeck, L. Minter, P. Chakrabarty, K. Felsenstein, T. Kukar, G. Maharvi, A. Fauq, B.A. Osborne, and T.E. Golde Transient pharmacologic lowering of Abeta production prior to deposition results in sustained reduction of amyloid plaque pathology Mol. Neurodegener. 7 2012 39
54. M. Garcia-Alloza, M. Subramanian, D. Thyssen, L.A. Borrelli, A. Fauq, P. Das, T.E. Golde, B.T. Hyman, and B.J. Bacskai Existing plaques and neuritic abnormalities in APP:PS1 mice are not affected by administration of the gamma-secretase inhibitor LY-411575 Mol. Neurodegener. 4 2009 19
55. N.F. Schor What the halted phase III gamma-secretase inhibitor trial may (or may not) be telling us Ann. Neurol. 69 2011 237 239
56. J. Cummings What can be inferred from the interruption of the semagacestat trial for treatment of Alzheimer's disease? Biol. Psychiatry 68 2010 876 878
57. K. Samson NerveCenter: Phase III Alzheimer trial halted: search for therapeutic biomarkers continues Ann. Neurol. 68 2010 A9 A12
58. A. Extance Alzheimer's failure raises questions about disease-modifying strategies Nat. Rev. Drug Discov. 9 2010 749 751
59. P. Rizzo, C. Osipo, K. Foreman, T. Golde, B. Osborne, and L. Miele Rational targeting of Notch signaling in cancer Oncogene 27 2008 5124 5131
60. T. Palomero, and A. Ferrando Therapeutic targeting of NOTCH1 signaling in T-cell acute lymphoblastic leukemia Clin. Lymphoma Myeloma 9 Suppl. 3 2009 S205 S210
61. T. Li, H. Wen, C. Brayton, P. Das, L.A. Smithson, A. Fauq, X. Fan, B.J. Crain, D.L. Price, T.E. Golde, C.G. Eberhart, and P.C. Wong Epidermal growth factor receptor and notch pathways participate in the tumor suppressor function of gamma-secretase J. Biol. Chem. 282 2007 32264 32273 (Pubitemid 350106457)
62. M. Okochi, H. Steiner, A. Fukumori, H. Tanii, T. Tomita, T. Tanaka, T. Iwatsubo, T. Kudo, M. Takeda, and C. Haass Presenilins mediate a dual intramembranous gamma-secretase cleavage of Notch-1 EMBO J. 21 2002 5408 5416 (Pubitemid 35231020)
63. Y. Xiao, Y. Ye, X. Zou, S. Jones, K. Yearsley, B. Shetuni, J. Tellez, and S.H. Barsky The lymphovascular embolus of inflammatory breast cancer exhibits a Notch 3 addiction Oncogene 30 2011 287 300
64. P. Wei, M. Walls, M. Qiu, R. Ding, R.H. Denlinger, A. Wong, K. Tsaparikos, J.P. Jani, N. Hosea, M. Sands, S. Randolph, and T. Smeal Evaluation of selective gamma-secretase inhibitor PF-03084014 for its antitumor efficacy and gastrointestinal safety to guide optimal clinical trial design Mol. Cancer Ther. 9 2010 1618 1628
65. M. Wang, L. Wu, L. Wang, and X. Xin Down-regulation of Notch1 by gamma-secretase inhibition contributes to cell growth inhibition and apoptosis in ovarian cancer cells A2780 Biochem. Biophys. Res. Commun. 393 2010 144 149
66. G. Peignon, A. Durand, W. Cacheux, O. Ayrault, B. Terris, P. Laurent-Puig, N.F. Shroyer, I. Van Seuningen, T. Honjo, C. Perret, and B. Romagnolo Complex interplay between beta-catenin signalling and Notch effectors in intestinal tumorigenesis Gut 60 2011 166 176
67. S. Guo, M. Liu, and R.R. Gonzalez-Perez Role of Notch and its oncogenic signaling crosstalk in breast cancer Biochim. Biophys. Acta 1815 2011 197 213
68. J.W. Watters, C. Cheng, P.K. Majumder, R. Wang, S. Yalavarthi, C. Meeske, L. Kong, W. Sun, J. Lin, J. Heyer, C. Ware, C. Winter, J.F. Reilly, T. Demuth, S. Clark, M.I. Chiu, M.O. Robinson, N. Kohl, and K. Kannan De novo discovery of a gamma-secretase inhibitor response signature using a novel in vivo breast tumor model Cancer Res. 69 2009 8949 8957
69. V. Rodilla, A. Villanueva, A. Obrador-Hevia, A. Robert-Moreno, V. Fernandez-Majada, A. Grilli, N. Lopez-Bigas, N. Bellora, M.M. Alba, F. Torres, M. Dunach, X. Sanjuan, S. Gonzalez, T. Gridley, G. Capella, A. Bigas, and L. Espinosa Jagged1 is the pathological link between Wnt and Notch pathways in colorectal cancer Proc. Natl. Acad. Sci. U. S. A. 106 2009 6315 6320
70. N. Rahimi, T.E. Golde, and R.D. Meyer Identification of ligand-induced proteolytic cleavage and ectodomain shedding of VEGFR-1/FLT1 in leukemic cancer cells Cancer Res. 69 2009 2607 2614
71. M.E. Mullendore, J.B. Koorstra, Y.M. Li, G.J. Offerhaus, X. Fan, C.M. Henderson, W. Matsui, C.G. Eberhart, A. Maitra, and G. Feldmann Ligand-dependent Notch signaling is involved in tumor initiation and tumor maintenance in pancreatic cancer Clin. Cancer Res. 15 2009 2291 2301
72. F. Engin, T. Bertin, O. Ma, M.M. Jiang, L. Wang, R.E. Sutton, L.A. Donehower, and B. Lee Notch signaling contributes to the pathogenesis of human osteosarcomas Hum. Mol. Genet. 18 2009 1464 1470
73. R.D. Meng, C.C. Shelton, Y.M. Li, L.X. Qin, D. Notterman, P.B. Paty, and G.K. Schwartz Gamma-secretase inhibitors abrogate oxaliplatin-induced activation of the Notch-1 signaling pathway in colon cancer cells resulting in enhanced chemosensitivity Cancer Res. 69 2009 573 582
74. J.H. Choi, J.T. Park, B. Davidson, P.J. Morin, M. Shih Ie, and T.L. Wang Jagged-1 and Notch3 juxtacrine loop regulates ovarian tumor growth and adhesion Cancer Res. 68 2008 5716 5723
75. C.W. Lee, C.M. Raskett, I. Prudovsky, and D.C. Altieri Molecular dependence of estrogen receptor-negative breast cancer on a notch-survivin signaling axis Cancer Res. 68 2008 5273 5281
76. P. Zhang, Y. Yang, P.A. Zweidler-McKay, and D.P. Hughes Critical role of notch signaling in osteosarcoma invasion and metastasis Clin. Cancer Res. 14 2008 2962 2969
77. J.H. van Es, and H. Clevers Notch and Wnt inhibitors as potential new drugs for intestinal neoplastic disease Trends Mol. Med. 11 2005 496 502 (Pubitemid 41653290)
78. L. Miele, H. Miao, and B.J. Nickoloff NOTCH signaling as a novel cancer therapeutic target Curr. Cancer Drug Targets 6 2006 313 323 (Pubitemid 43961866)
79. W.S. Pear, and J.C. Aster T cell acute lymphoblastic leukemia/lymphoma: a human cancer commonly associated with aberrant NOTCH1 signaling Curr. Opin. Hematol. 11 2004 426 433 (Pubitemid 39491437)
80. K.A. Hassan, L. Wang, H. Korkaya, G. Chen, I. Maillard, D.G. Beer, G.P. Kalemkerian, and M.S. Wicha Notch pathway activity identifies cells with cancer stem cell-like properties and correlates with worse survival in lung adenocarcinoma Clin. Cancer Res. 19 2013 1972 1980
81. S. Yabuuchi, S.G. Pai, N.R. Campbell, R.F. de Wilde, E. De Oliveira, P. Korangath, M.M. Streppel, Z.A. Rasheed, M. Hidalgo, A. Maitra, and N.V. Rajeshkumar Notch signaling pathway targeted therapy suppresses tumor progression and metastatic spread in pancreatic cancer Cancer Lett. 335 1 2013 41 51
82. J.E. Roderick, G. Gonzalez-Perez, C.A. Kuksin, A. Dongre, E.R. Roberts, J. Srinivasan, C. Andrzejewski Jr., A.H. Fauq, T.E. Golde, L. Miele, and L.M. Minter Therapeutic targeting of NOTCH signaling ameliorates immune-mediated bone marrow failure of aplastic anemia J. Exp. Med. 2013 (in press)
83. L.M. Minter, D.M. Turley, P. Das, H.M. Shin, I. Joshi, R.G. Lawlor, O.H. Cho, T. Palaga, S. Gottipati, J.C. Telfer, L. Kostura, A.H. Fauq, K. Simpson, K.A. Such, L. Miele, T.E. Golde, S.D. Miller, and B.A. Osborne Inhibitors of gamma-secretase block in vivo and in vitro T helper type 1 polarization by preventing Notch upregulation of Tbx21 Nat. Immunol. 6 2005 680 688 (Pubitemid 41716741)
84. K. Piggott, J. Deng, K. Warrington, B. Younge, J.T. Kubo, M. Desai, J.J. Goronzy, and C.M. Weyand Blocking the NOTCH pathway inhibits vascular inflammation in large-vessel vasculitis Circulation 123 2011 309 318
85. Z. Ablonczy, A. Prakasam, J. Fant, A. Fauq, C. Crosson, and K. Sambamurti Pigment epithelium-derived factor maintains retinal pigment epithelium function by inhibiting vascular endothelial growth factor-R2 signaling through gamma-secretase J. Biol. Chem. 284 2009 30177 30186
86. C.L. Lin, F.S. Wang, Y.C. Hsu, C.N. Chen, M.J. Tseng, M.A. Saleem, P.J. Chang, and J.Y. Wang Modulation of notch-1 signaling alleviates vascular endothelial growth factor-mediated diabetic nephropathy Diabetes 59 2010 1915 1925
87. T. Niranjan, B. Bielesz, A. Gruenwald, M.P. Ponda, J.B. Kopp, D.B. Thomas, and K. Susztak The Notch pathway in podocytes plays a role in the development of glomerular disease Nat. Med. 14 2008 290 298 (Pubitemid 351347919)
88. R. Huang, Q. Zhou, P. Veeraragoo, H. Yu, and Z. Xiao Notch2/Hes-1 pathway plays an important role in renal ischemia and reperfusion injury-associated inflammation and apoptosis and the gamma-secretase inhibitor DAPT has a nephroprotective effect Ren. Fail. 33 2011 207 216
89. T.V. Arumugam, S.L. Chan, D.G. Jo, G. Yilmaz, S.C. Tang, A. Cheng, M. Gleichmann, E. Okun, V.D. Dixit, S. Chigurupati, M.R. Mughal, X. Ouyang, L. Miele, T. Magnus, S. Poosala, D.N. Granger, and M.P. Mattson Gamma secretase-mediated Notch signaling worsens brain damage and functional outcome in ischemic stroke Nat. Med. 12 2006 621 623 (Pubitemid 43865228)
90. D.J. Loane, A. Pocivavsek, C.E. Moussa, R. Thompson, Y. Matsuoka, A.I. Faden, G.W. Rebeck, and M.P. Burns Amyloid precursor protein secretases as therapeutic targets for traumatic brain injury Nat. Med. 15 2009 377 379
91. K. Mizutari, M. Fujioka, M. Hosoya, N. Bramhall, H.J. Okano, H. Okano, and A.S. Edge Notch inhibition induces cochlear hair cell regeneration and recovery of hearing after acoustic trauma Neuron 77 2013 58 69
92. B. Bielesz, Y. Sirin, H. Si, T. Niranjan, A. Gruenwald, S. Ahn, H. Kato, J. Pullman, M. Gessler, V.H. Haase, and K. Susztak Epithelial Notch signaling regulates interstitial fibrosis development in the kidneys of mice and humans J. Clin. Invest. 120 2010 4040 4054
93. L. Miele, T. Golde, and B. Osborne Notch signaling in cancer Curr. Mol. Med. 6 2006 905 918 (Pubitemid 44883940)
94. B. Purow Notch inhibition as a promising new approach to cancer therapy Adv. Exp. Med. Biol. 727 2012 305 319
95. L.A. Milner, and A. Bigas Notch as a mediator of cell fate determination in hematopoiesis: evidence and speculation Blood 93 1999 2431 2448 (Pubitemid 29181173)
96. B. Osborne, and L. Miele Notch and the immune system Immunity 11 1999 653 663 (Pubitemid 30030705)
97. J.C. Aster, and W.S. Pear Notch signaling in leukemia Curr. Opin. Hematol. 8 2001 237 244 (Pubitemid 32762967)
98. I. Maillard, S.H. Adler, and W.S. Pear Notch and the immune system Immunity 19 2003 781 791 (Pubitemid 37542299)
99. K. Vo, B. Amarasinghe, K. Washington, A. Gonzalez, J. Berlin, and T.P. Dang Targeting notch pathway enhances rapamycin antitumor activity in pancreas cancers through PTEN phosphorylation Mol. Cancer 10 2011 138
100. J.W. Gu, P. Rizzo, A. Pannuti, T. Golde, B. Osborne, and L. Miele Notch signals in the endothelium and cancer "stem-like" cells: opportunities for cancer therapy Vasc. Cell 4 2012 7
101. R. Wang, P. Tang, P. Wang, R.E. Boissy, and H. Zheng Regulation of tyrosinase trafficking and processing by presenilins: partial loss of function by familial Alzheimer's disease mutation Proc. Natl. Acad. Sci. U. S. A. 103 2006 353 358 (Pubitemid 43122404)
102. S. Guo, and R.R. Gonzalez-Perez Notch, IL-1 and leptin crosstalk outcome (NILCO) is critical for leptin-induced proliferation, migration and VEGF/VEGFR-2 expression in breast cancer PLoS One 6 2011 e21467
103. A.G. Clementz, A. Rogowski, K. Pandya, L. Miele, and C. Osipo NOTCH-1 and NOTCH-4 are novel gene targets of PEA3 in breast cancer: novel therapeutic implications Breast Cancer Res. 13 2011 R63
104. B. De Strooper, and W. Annaert Novel research horizons for presenilins and gamma-secretases in cell biology and disease Annu. Rev. Cell Dev. Biol. 26 2010 235 260
105. B. Zhao, M. Yu, M. Neitzel, J. Marugg, J. Jagodzinski, M. Lee, K. Hu, D. Schenk, T. Yednock, and G. Basi Identification of gamma-secretase inhibitor potency determinants on presenilin J. Biol. Chem. 283 2008 2927 2938
106. T. Borgegard, S. Gustavsson, C. Nilsson, S. Parpal, R. Klintenberg, A.L. Berg, S. Rosqvist, L. Serneels, S. Svensson, F. Olsson, S. Jin, H. Yan, J. Wanngren, A. Jureus, A. Ridderstad-Wollberg, P. Wollberg, K. Stockling, H. Karlstrom, A. Malmberg, J. Lund, P.I. Arvidsson, B. De Strooper, U. Lendahl, and J. Lundkvist Alzheimer's disease: presenilin 2-sparing gamma-secretase inhibition is a tolerable Abeta peptide-lowering strategy J. Neurosci. 32 2012 17297 17305
107. L. Serneels, J. Van Biervliet, K. Craessaerts, T. Dejaegere, K. Horre, T. Van Houtvin, H. Esselmann, S. Paul, M.K. Schafer, O. Berezovska, B.T. Hyman, B. Sprangers, R. Sciot, L. Moons, M. Jucker, Z. Yang, P.C. May, E. Karran, J. Wiltfang, R. D'Hooge, and B. De Strooper Gamma-secretase heterogeneity in the Aph1 subunit: relevance for Alzheimer's disease Science 324 2009 639 642
108. J. Lee, L. Song, G. Terracina, T. Bara, H. Josien, T. Asberom, T.K. Sasikumar, D.A. Burnett, J. Clader, E.M. Parker, and L. Zhang Identification of Presenilin 1 selective gamma-secretase inhibitors with reconstituted gamma-secretase complexes Biochemistry 50 22 2011 4973 4980
109. L. Placanica, J.W. Chien, and Y.M. Li Characterization of an atypical gamma-secretase complex from hematopoietic origin Biochemistry 49 2010 2796 2804
110. H. Wang, W.J. Luo, Y.W. Zhang, Y.M. Li, G. Thinakaran, P. Greengard, and H. Xu Presenilins and gamma-secretase inhibitors affect intracellular trafficking and cell surface localization of the gamma-secretase complex components J. Biol. Chem. 279 2004 40560 40566 (Pubitemid 39287647)
111. M.S. Wolfe Gamma-secretase as a target for Alzheimer's disease Adv. Pharmacol. 64 2012 127 153
112. S.C. Mayer, A.F. Kreft, B. Harrison, M. Abou-Gharbia, M. Antane, S. Aschmies, K. Atchison, M. Chlenov, D.C. Cole, T. Comery, G. Diamantidis, J. Ellingboe, K. Fan, R. Galante, C. Gonzales, D.M. Ho, M.E. Hoke, Y. Hu, D. Huryn, U. Jain, M. Jin, K. Kremer, D. Kubrak, M. Lin, P. Lu, R. Magolda, R. Martone, W. Moore, A. Oganesian, M.N. Pangalos, A. Porte, P. Reinhart, L. Resnick, D.R. Riddell, J. Sonnenberg-Reines, J.R. Stock, S.C. Sun, E. Wagner, T. Wang, K. Woller, Z. Xu, M.M. Zaleska, J. Zeldis, M. Zhang, H. Zhou, and J.S. Jacobsen Discovery of Begacestat, a Notch-1-sparing gamma-secretase inhibitor for the treatment of Alzheimer's disease J. Med. Chem. 51 23 2008 7348 7351
113. X.M. Ye, A.W. Konradi, J. Smith, D.L. Aubele, A.W. Garofalo, J. Marugg, M.L. Neitzel, C.M. Semko, H.L. Sham, M. Sun, A.P. Truong, J. Wu, H. Zhang, E. Goldbach, J.M. Sauer, E.F. Brigham, M. Bova, and G.S. Basi Discovery of a novel sulfonamide-pyrazolopiperidine series as potent and efficacious gamma-secretase inhibitors (Part II) Bioorg. Med. Chem. Lett. 20 2010 3502 3506
114. G.S. Basi, S. Hemphill, E.F. Brigham, A. Liao, D.L. Aubele, J. Baker, R. Barbour, M. Bova, X.H. Chen, M.S. Dappen, T. Eichenbaum, E. Goldbach, J. Hawkinson, R. Lawler-Herbold, K. Hu, T. Hui, J.J. Jagodzinski, P.S. Keim, D. Kholodenko, L.H. Latimer, M. Lee, J. Marugg, M.N. Mattson, S. McCauley, J.L. Miller, R. Motter, L. Mutter, M.L. Neitzel, H. Ni, L. Nguyen, K. Quinn, L. Ruslim, C.M. Semko, P. Shapiro, J. Smith, F. Soriano, B. Szoke, K. Tanaka, P. Tang, J.A. Tucker, X.M. Ye, M. Yu, J. Wu, Y.Z. Xu, A.W. Garofalo, J.M. Sauer, A.W. Konradi, D. Ness, G. Shopp, M.A. Pleiss, S.B. Freedman, and D. Schenk Amyloid precursor protein selective gamma-secretase inhibitors for treatment of Alzheimer's disease Alzheimers Res. Ther. 2 2010 36
115. C.F. Albright, R.C. Dockens, J.E. Meredith Jr., R.E. Olson, R. Slemmon, K.A. Lentz, J.S. Wang, R.R. Denton, G. Pilcher, P.W. Rhyne, J.J. Raybon, D.M. Barten, C. Burton, J.H. Toyn, S. Sankaranarayanan, C. Polson, V. Guss, R. White, F. Simutis, T. Sanderson, K.W. Gillman, J.E. Starrett Jr., J. Bronson, O. Sverdlov, S.P. Huang, L. Castaneda, H. Feldman, V. Coric, R. Zaczek, J.E. Macor, J. Houston, R.M. Berman, and G. Tong Pharmacodynamics of selective inhibition of gamma-secretase by avagacestat J. Pharmacol. Exp. Ther. 344 2013 686 695
116. G. Tong, L. Castaneda, J.S. Wang, O. Sverdlov, S.P. Huang, R. Slemmon, H. Gu, O. Wong, H. Li, R.M. Berman, C. Smith, C. Albright, and R.C. Dockens Effects of single doses of avagacestat (BMS-708163) on cerebrospinal fluid Abeta levels in healthy young men Clin. Drug Investig. 32 2012 761 769
117. C.J. Crump, S.V. Castro, F. Wang, N. Pozdnyakov, T.E. Ballard, S.S. Sisodia, K.R. Bales, D.S. Johnson, and Y.M. Li BMS-708,163 targets presenilin and lacks notch-sparing activity Biochemistry 51 2012 7209 7211
118. V. Coric, C.H. van Dyck, S. Salloway, N. Andreasen, M. Brody, R.W. Richter, H. Soininen, S. Thein, T. Shiovitz, G. Pilcher, S. Colby, L. Rollin, R. Dockens, C. Pachai, E. Portelius, U. Andreasson, K. Blennow, H. Soares, C. Albright, H.H. Feldman, and R.M. Berman Safety and tolerability of the gamma-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease Arch. Neurol. 69 2012 1430 1440
119. M. Kurosumi, Y. Nishio, S. Osawa, H. Kobayashi, T. Iwatsubo, T. Tomita, and H. Miyachi Novel Notch-sparing gamma-secretase inhibitors derived from a peroxisome proliferator-activated receptor agonist library Bioorg. Med. Chem. Lett. 20 2010 5282 5285
120. L. Chavez-Gutierrez, L. Bammens, I. Benilova, A. Vandersteen, M. Benurwar, M. Borgers, S. Lismont, L. Zhou, S. Van Cleynenbreugel, H. Esselmann, J. Wiltfang, L. Serneels, E. Karran, H. Gijsen, J. Schymkowitz, F. Rousseau, K. Broersen, and B. De Strooper The mechanism of gamma-Secretase dysfunction in familial Alzheimer disease EMBO J. 31 2012 2261 2274
121. H. Karlstrom, A. Bergman, U. Lendahl, J. Naslund, and J. Lundkvist A sensitive and quantitative assay for measuring cleavage of presenilin substrates J. Biol. Chem. 277 2002 6763 6766 (Pubitemid 34953055)
122. P.L. Gunyuzlu, W.H. White, G.L. Davis, G.F. Hollis, and J.H. Toyn A yeast genetic assay for caspase cleavage of the amyloid-beta precursor protein Mol. Biotechnol. 15 2000 29 37 (Pubitemid 30451088)
123. A.F. Schott, M.D. Landis, G. Dontu, K.A. Griffith, R.M. Layman, I. Krop, L.A. Paskett, H. Wong, L.E. Dobrolecki, M.T. Lewis, A.M. Froehlich, J. Paranilam, D.F. Hayes, M.S. Wicha, and J.C. Chang Preclinical and clinical studies of gamma secretase inhibitors with docetaxel on human breast tumors Clin. Cancer Res. 19 2013 1512 1524
124. P.J. Real, V. Tosello, T. Palomero, M. Castillo, E. Hernando, E. de Stanchina, M.L. Sulis, K. Barnes, C. Sawai, I. Homminga, J. Meijerink, I. Aifantis, G. Basso, C. Cordon-Cardo, W. Ai, and A. Ferrando Gamma-secretase inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia Nat. Med. 15 2009 50 58
125. T.E. Golde, C.B. Eckman, and S.G. Younkin Biochemical detection of Abeta isoforms: implications for pathogenesis, diagnosis, and treatment of Alzheimer's disease Biochim. Biophys. Acta 1502 2000 172 187 (Pubitemid 30433866)
126. D. Selkoe, and R. Kopan Notch and Presenilin: regulated intramembrane proteolysis links development and degeneration Annu. Rev. Neurosci. 26 2003 565 597 (Pubitemid 37064944)
127. S.F. Lichtenthaler, N. Ida, G. Multhaup, C.L. Masters, and K. Beyreuther Mutations in the transmembrane domain of APP altering gamma-secretase specificity Biochemistry 36 1997 15396 15403 (Pubitemid 27528006)
128. S.F. Lichtenthaler, R. Wang, H. Grimm, S.N. Uljon, C.L. Masters, and K. Beyreuther Mechanism of the cleavage specificity of Alzheimer's disease gamma-secretase identified by phenylalanine-scanning mutagenesis of the transmembrane domain of the amyloid precursor protein Proc. Natl. Acad. Sci. U. S. A. 96 1999 3053 3058 (Pubitemid 29148842)
129. S.A. Sagi, C.B. Lessard, K.D. Winden, H. Maruyama, J.C. Koo, S. Weggen, T.L. Kukar, T.E. Golde, and E.H. Koo Substrate sequence influences gamma-secretase modulator activity, role of the transmembrane domain of the amyloid precursor protein J. Biol. Chem. 286 2011 39794 39803
130. T.L. Kukar, T.B. Ladd, P. Robertson, S.A. Pintchovski, B. Moore, M.A. Bann, Z. Ren, K. Jansen-West, K. Malphrus, S. Eggert, H. Maruyama, B.A. Cottrell, P. Das, G.S. Basi, E.H. Koo, and T.E. Golde Lysine 624 of the amyloid precursor protein (APP) is a critical determinant of amyloid beta peptide length: support for a sequential model of gamma-secretase intramembrane proteolysis and regulation by the amyloid beta precursor protein (APP) juxtamembrane region J. Biol. Chem. 286 2011 39804 39812
131. L. Tarassishin, Y.I. Yin, B. Bassit, and Y.M. Li Processing of Notch and amyloid precursor protein by gamma-secretase is spatially distinct Proc. Natl. Acad. Sci. U. S. A. 101 2004 17050 17055 (Pubitemid 39627772)
132. S. Wahrle, P. Das, A.C. Nyborg, C. McLendon, M. Shoji, T. Kawarabayashi, L.H. Younkin, S.G. Younkin, and T.E. Golde Cholesterol-dependent gamma-secretase activity in buoyant cholesterol-rich membrane microdomains Neurobiol. Dis. 9 2002 11 23 (Pubitemid 34174561)
133. K.S. Vetrivel, H. Cheng, W. Lin, T. Sakurai, T. Li, N. Nukina, P.C. Wong, H. Xu, and G. Thinakaran Association of gamma-secretase with lipid rafts in post-golgi and endosome membranes J. Biol. Chem. 279 43 2004 44945 44954 (Pubitemid 39430908)
134. K.S. Vetrivel, P. Gong, J.W. Bowen, H. Cheng, Y. Chen, M. Carter, P.D. Nguyen, L. Placanica, F.T. Wieland, Y.M. Li, M.Z. Kounnas, and G. Thinakaran Dual roles of the transmembrane protein p23/TMP21 in the modulation of amyloid precursor protein metabolism Mol. Neurodegener. 2 2007 4
135. T. Wakabayashi, K. Craessaerts, L. Bammens, M. Bentahir, F. Borgions, P. Herdewijn, A. Staes, E. Timmerman, J. Vandekerckhove, E. Rubinstein, C. Boucheix, K. Gevaert, and B. De Strooper Analysis of the gamma-secretase interactome and validation of its association with tetraspanin-enriched microdomains Nat. Cell Biol. 11 2009 1340 1346
136. J.Y. Hur, H. Welander, H. Behbahani, M. Aoki, J. Franberg, B. Winblad, S. Frykman, and L.O. Tjernberg Active gamma-secretase is localized to detergent-resistant membranes in human brain FEBS J. 275 2008 1174 1187 (Pubitemid 351342213)
137. R. Wang, D. Sweeney, S.E. Gandy, and S.S. Sisodia The profile of soluble amyloid beta protein in cultured cell media. Detection and quantification of amyloid beta protein and variants by immunoprecipitation-mass spectrometry J. Biol. Chem. 271 1996 31894 31902 (Pubitemid 26422211)
138. S.G. Younkin The role of A beta 42 in Alzheimer's disease J. Physiol. Paris 92 1998 289 292
139. T.E. Golde The pathogenesis of Alzheimer's disease and the role of Abeta42 CNS Spectr. 12 2007 4 6
140. D.J. Selkoe Alzheimer's disease: genes, proteins, and therapy Physiol. Rev. 81 2001 741 766 (Pubitemid 32267077)
141. C.R. Jack Jr., V.J. Lowe, S.D. Weigand, H.J. Wiste, M.L. Senjem, D.S. Knopman, M.M. Shiung, J.L. Gunter, B.F. Boeve, B.J. Kemp, M. Weiner, and R.C. Petersen Serial PIB and MRI in normal, mild cognitive impairment and Alzheimer's disease: implications for sequence of pathological events in Alzheimer's disease Brain 2009
142. J.T. Jarrett, E.P. Berger, J.T. Jarret, and P.T. Lansbury Jr. The carboxy terminus of ß amyloid protein is critical for the seeding of amyloid formation: implications for pathogenesis of Alzheimer's disease Biochemistry 32 1993 4693 4697 (Pubitemid 23162022)
143. J.T. Jarrett, and P.T. Lansbury Jr. Seeding "one dimensional crystallization" of amyloid: a pathogenic mechanism in Alzheimer's disease and Scrapie? Cell 73 1993 1055 1058 (Pubitemid 23180480)
144. K. Duff, C. Eckman, C. Zehr, X. Yu, C.M. Prada, J. Perez-tur, M. Hutton, L. Buee, Y. Harigaya, D. Yager, D. Morgan, M.N. Gordon, L. Holcomb, L. Refolo, B. Zenk, J. Hardy, and S. Younkin Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1 Nature 383 1996 710 713 (Pubitemid 26360645)
145. D. Games, D. Adams, R. Alessandrini, R. Barbour, P. Berthelette, C. Blackwell, T. Carr, J. Clemens, T. Donaldson, F. Gillespie, T. Guido, S. Hagoplan, K. Johnson-Wood, K. Khan, M. Lee, P. Leibowitz, I. Lieberburg, S. Little, E. Masliah, L. McConlogue, M. Montoya-Zavala, L. Mucke, L. Paganini, E. Penniman, M. Power, D. Schenk, P. Seubert, B. Snyder, F. Sorlano, H. Tan, J. Vitale, S. Wadsworth, B. Wolozin, and J. Zhao Alzheimer-type neuropathology in transgenic mice overexpressing V717F ß-amyloid precursor protein Nature 373 1995 523 527
146. K. Iijima, H.P. Liu, A.S. Chiang, S.A. Hearn, M. Konsolaki, and Y. Zhong Dissecting the pathological effects of human Abeta40 and Abeta42 in Drosophila: a potential model for Alzheimer's disease Proc. Natl. Acad. Sci. U. S. A. 101 2004 6623 6628 (Pubitemid 38586024)
147. I. Greeve, D. Kretzschmar, J.A. Tschape, A. Beyn, C. Brellinger, M. Schweizer, R.M. Nitsch, and R. Reifegerste Age-dependent neurodegeneration and Alzheimer-amyloid plaque formation in transgenic Drosophila J. Neurosci. 24 2004 3899 3906 (Pubitemid 38544216)
148. E. McGowan, F. Pickford, J. Kim, L. Onstead, J. Eriksen, C. Yu, L. Skipper, M.P. Murphy, J. Beard, P. Das, K. Jansen, M. Delucia, W.L. Lin, G. Dolios, R. Wang, C.B. Eckman, D.W. Dickson, M. Hutton, J. Hardy, and T. Golde Abeta42 is essential for parenchymal and vascular amyloid deposition in mice Neuron 47 2005 191 199 (Pubitemid 41019251)
149. M.C. Herzig, D.T. Winkler, P. Burgermeister, M. Pfeifer, E. Kohler, S.D. Schmidt, S. Danner, D. Abramowski, C. Sturchler-Pierrat, K. Burki, S.G. van Duinen, M.L. Maat-Schieman, M. Staufenbiel, P.M. Mathews, and M. Jucker Abeta is targeted to the vasculature in a mouse model of hereditary cerebral hemorrhage with amyloidosis Nat. Neurosci. 7 2004 954 960 (Pubitemid 39129504)
150. S. Weggen, J.L. Eriksen, S.A. Sagi, C.U. Pietrzik, V. Ozols, A. Fauq, T.E. Golde, and E.H. Koo Evidence that nonsteroidal anti-inflammatory drugs decrease amyloid beta 42 production by direct modulation of gamma-secretase activity J. Biol. Chem. 278 2003 31831 31837 (Pubitemid 37048365)
151. J.L. Eriksen, S.A. Sagi, T.E. Smith, S. Weggen, P. Das, D.C. McLendon, V.V. Ozols, K.W. Jessing, K.H. Zavitz, E.H. Koo, and T.E. Golde NSAIDs and enantiomers of flurbiprofen target gamma-secretase and lower Abeta 42 in vivo J. Clin. Invest. 112 2003 440 449 (Pubitemid 38063773)
152. S. Weggen, J.L. Eriksen, P. Das, S.A. Sagi, R. Wang, C.U. Pietrzik, K.A. Findlay, T.E. Smith, M.P. Murphy, T. Bulter, D.E. Kang, N. Marquez-Sterling, T.E. Golde, and E.H. Koo A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity Nature 414 2001 212 216 (Pubitemid 33051236)
153. T. Kukar, M.P. Murphy, J.L. Eriksen, S.A. Sagi, S. Weggen, T.E. Smith, T. Ladd, M.A. Khan, R. Kache, J. Beard, M. Dodson, S. Merit, V.V. Ozols, P.Z. Anastasiadis, P. Das, A. Fauq, E.H. Koo, and T.E. Golde Diverse compounds mimic Alzheimer disease-causing mutations by augmenting Abeta42 production Nat. Med. 11 2005 545 550 (Pubitemid 40685978)
154. L. Gasparini, L. Rusconi, H. Xu, P. del Soldato, and E. Ongini Modulation of beta-amyloid metabolism by non-steroidal anti-inflammatory drugs in neuronal cell cultures J. Neurochem. 88 2004 337 348 (Pubitemid 38084550)
155. K. Rogers, K.M. Felsenstein, L. Hrdlicka, Z. Tu, F. Albayya, W. Lee, S. Hopp, M.J. Miller, D. Spaulding, Z. Yang, H. Hodgdon, S. Nolan, M. Wen, D. Costa, J.F. Blain, E. Freeman, B. De Strooper, V. Vulsteke, L. Scrocchi, H. Zetterberg, E. Portelius, B. Hutter-Paier, D. Havas, M. Ahlijanian, D. Flood, L. Leventhal, G. Shapiro, H. Patzke, R. Chesworth, and G. Koenig Modulation of gamma-secretase by EVP-0015962 reduces amyloid deposition and behavioral deficits in Tg2576 mice Mol. Neurodegener. 7 2012 61
156. B.P. Imbimbo, E. Del Giudice, D. Colavito, A. D'Arrigo, M. Dalle Carbonare, G. Villetti, F. Facchinetti, R. Volta, V. Pietrini, M.F. Baroc, L. Serneels, B. De Strooper, and A. Leon 1-(3′,4′-Dichloro-2-fluoro[1, 1′-biphenyl]-4-yl)-cyclopropanecarboxylic acid (CHF5074), a novel gamma-secretase modulator, reduces brain beta-amyloid pathology in a transgenic mouse model of Alzheimer's disease without causing peripheral toxicity J. Pharmacol. Exp. Ther. 323 2007 822 830 (Pubitemid 350146064)
157. B.P. Imbimbo, E. Del Giudice, V. Cenacchi, R. Volta, G. Villetti, F. Facchinetti, B. Riccardi, P. Puccini, N. Moretto, F. Grassi, S. Ottonello, and A. Leon In vitro and in vivo profiling of CHF5022 and CHF5074 Two beta-amyloid1-42 lowering agents Pharmacol. Res. 55 2007 318 328 (Pubitemid 46533934)
158. E. Portelius, B. Van Broeck, U. Andreasson, M.K. Gustavsson, M. Mercken, H. Zetterberg, H. Borghys, and K. Blennow Acute effect on the Abeta isoform pattern in CSF in response to gamma-secretase modulator and inhibitor treatment in dogs J. Alzheimers Dis. 21 2010 1005 1012
159. J. Qin, P. Dhondi, X. Huang, M. Mandal, Z. Zhao, D. Pissarnitski, W. Zhou, R. Aslanian, Z. Zhu, W. Greenlee, J. Clader, L. Zhang, M. Cohen-Williams, N. Jones, L. Hyde, and A. Palani Discovery of fused 5,6-bicyclic heterocycles as gamma-secretase modulators Bioorg. Med. Chem. Lett. 21 2011 664 669
160. H.J. Gijsen, and M. Mercken Gamma-secretase modulators: can we combine potency with safety? Int. J. Alzheimers Dis. 2012 2012 295207
161. A. Hall, R.L. Elliott, G.M. Giblin, I. Hussain, J. Musgrave, A. Naylor, R. Sasse, and B. Smith Piperidine-derived gamma-secretase modulators Bioorg. Med. Chem. Lett. 20 2010 1306 1311
162. M.G. Stanton, J. Hubbs, D. Sloman, C. Hamblett, P. Andrade, M. Angagaw, G. Bi, R.M. Black, J. Crispino, J.C. Cruz, E. Fan, G. Farris, B.L. Hughes, C.M. Kenific, R.E. Middleton, G. Nikov, P. Sajonz, S. Shah, N. Shomer, A.A. Szewczak, F. Tanga, M.T. Tudge, M. Shearman, and B. Munoz Fluorinated piperidine acetic acids as gamma-secretase modulators Bioorg. Med. Chem. Lett. 20 2010 755 758
163. H. Li, J. Qin, P. Dhondi, W. Zhou, M. Vicarel, T. Bara, D. Cole, H. Josien, D. Pissarnitski, Z. Zhu, A. Palani, R. Aslanian, J. Clader, M. Czarniecki, W. Greenlee, M. Cohen-Williams, L. Hyde, L. Song, L. Zhang, I. Chu, and X. Huang The discovery of fused oxadiazepines as gamma secretase modulators for treatment of Alzheimer's disease Bioorg. Med. Chem. Lett. 23 2013 466 471
164. Z.Y. Sun, T. Asberom, T. Bara, C. Bennett, D. Burnett, I. Chu, J. Clader, M. Cohen-Williams, D. Cole, M. Czarniecki, J. Durkin, G. Gallo, W. Greenlee, H. Josien, X. Huang, L. Hyde, N. Jones, I. Kazakevich, H. Li, X. Liu, J. Lee, M. Maccoss, M.B. Mandal, T. McCracken, A. Nomeir, R. Mazzola, A. Palani, E.M. Parker, D.A. Pissarnitski, J. Qin, L. Song, G. Terracina, M. Vicarel, J. Voigt, R. Xu, L. Zhang, Q. Zhang, Z. Zhao, X. Zhu, and Z. Zhu Cyclic hydroxyamidines as amide isosteres: discovery of oxadiazolines and oxadiazines as potent and highly efficacious gamma-secretase modulators in vivo J. Med. Chem. 55 2012 489 502
165. A. Rivkin, S.P. Ahearn, S.M. Chichetti, C.L. Hamblett, Y. Garcia, M. Martinez, J.L. Hubbs, M.H. Reutershan, M.H. Daniels, P. Siliphaivanh, K.M. Otte, C. Li, A. Rosenau, L.M. Surdi, J. Jung, B.L. Hughes, J.L. Crispino, G.N. Nikov, R.E. Middleton, C.M. Moxham, A.A. Szewczak, S. Shah, L.Y. Moy, C.M. Kenific, F. Tanga, J.C. Cruz, P. Andrade, M.H. Angagaw, N.H. Shomer, T. Miller, B. Munoz, and M.S. Shearman Purine derivatives as potent gamma-secretase modulators Bioorg. Med. Chem. Lett. 20 2010 2279 2282
166. A. Rivkin, S.P. Ahearn, S.M. Chichetti, Y.R. Kim, C. Li, A. Rosenau, S.D. Kattar, J. Jung, S. Shah, B.L. Hughes, J.L. Crispino, R.E. Middleton, A.A. Szewczak, B. Munoz, and M.S. Shearman Piperazinyl pyrimidine derivatives as potent gamma-secretase modulators Bioorg. Med. Chem. Lett. 20 2010 1269 1271
167. T. Lubbers, A. Flohr, S. Jolidon, P. David-Pierson, H. Jacobsen, L. Ozmen, and K. Baumann Aminothiazoles as gamma-secretase modulators Bioorg. Med. Chem. Lett. 21 2011 6554 6558
168. Z. Xin, H. Peng, A. Zhang, T. Talreja, G. Kumaravel, L. Xu, E. Rohde, M.Y. Jung, M.N. Shackett, D. Kocisko, S. Chollate, A.W. Dunah, P.A. Snodgrass-Belt, H.M. Arnold, A.G. Taveras, K.J. Rhodes, and R.H. Scannevin Discovery of 4-aminomethylphenylacetic acids as gamma-secretase modulators via a scaffold design approach Bioorg. Med. Chem. Lett. 21 2011 7277 7280
169. F. Bischoff, D. Berthelot, M. De Cleyn, G. Macdonald, G. Minne, D. Oehlrich, S. Pieters, M. Surkyn, A.A. Trabanco, G. Tresadern, S. Van Brandt, I. Velter, M. Zaja, H. Borghys, C. Masungi, M. Mercken, and H.J. Gijsen Design and synthesis of a novel series of bicyclic heterocycles as potent gamma-secretase modulators J. Med. Chem. 55 2012 9089 9106
170. B. Van Broeck, J.M. Chen, G. Treton, M. Desmidt, C. Hopf, N. Ramsden, E. Karran, M. Mercken, and A. Rowley Chronic treatment with a novel gamma-secretase modulator, JNJ-40418677, inhibits amyloid plaque formation in a mouse model of Alzheimer's disease Br. J. Pharmacol. 163 2011 375 389
171. M.Z. Kounnas, A.M. Danks, S. Cheng, C. Tyree, E. Ackerman, X. Zhang, K. Ahn, P. Nguyen, D. Comer, L. Mao, C. Yu, D. Pleynet, P.J. Digregorio, G. Velicelebi, K.A. Stauderman, W.T. Comer, W.C. Mobley, Y.M. Li, S.S. Sisodia, R.E. Tanzi, and S.L. Wagner Modulation of gamma-secretase reduces beta-amyloid deposition in a transgenic mouse model of Alzheimer's disease Neuron 67 2010 769 780
172. R. Narlawar, B.I. Perez Revuelta, K. Baumann, R. Schubenel, C. Haass, H. Steiner, and B. Schmidt N-Substituted carbazolyloxyacetic acids modulate Alzheimer associated gamma-secretase Bioorg. Med. Chem. Lett. 17 2007 176 182 (Pubitemid 44959962)
173. J.L. Hubbs, N.O. Fuller, W.F. Austin, R. Shen, S.P. Creaser, T.D. McKee, R.M. Loureiro, B. Tate, W. Xia, J. Ives, and B.S. Bronk Optimization of a natural product-based class of gamma-secretase modulators J. Med. Chem. 55 2012 9270 9282
174. R.M. Loureiro, J.A. Dumin, T.D. McKee, W.F. Austin, N.O. Fuller, J.L. Hubbs, R. Shen, J. Jonker, J. Ives, B.S. Bronk, and B. Tate Efficacy of SPI-1865, a novel gamma-secretase modulator, in multiple rodent models Alzheimers Res. Ther. 5 2013 19
175. R.M. Page, K. Baumann, M. Tomioka, B.I. Perez-Revuelta, A. Fukumori, H. Jacobsen, A. Flohr, T. Luebbers, L. Ozmen, H. Steiner, and C. Haass Generation of A 38 and A 42 is independently and differentially affected by familial alzheimer disease-associated presenilin mutations and {gamma}-secretase modulation J. Biol. Chem. 283 2008 677 683
176. E. Czirr, B.A. Cottrell, S. Leuchtenberger, T. Kukar, T.B. Ladd, H. Esselmann, S. Paul, R. Schubenel, J.W. Torpey, C.U. Pietrzik, T.E. Golde, J. Wiltfang, K. Baumann, E.H. Koo, and S. Weggen Independent generation of Abeta 42 and Abeta 38 peptide species by gamma-secretase J. Biol. Chem. 283 25 2008 17049 17054
177. S. Weggen, J.L. Eriksen, S.A. Sagi, C.U. Pietrzik, T.E. Golde, and E.H. Koo Abeta42-lowering nonsteroidal anti-inflammatory drugs preserve intramembrane cleavage of the amyloid precursor protein (APP) and ErbB-4 receptor and signaling through the APP intracellular domain J. Biol. Chem. 278 2003 30748 30754 (Pubitemid 36994581)
178. T.L. Kukar, T.B. Ladd, M.A. Bann, P.C. Fraering, R. Narlawar, G.M. Maharvi, B. Healy, R. Chapman, A.T. Welzel, R.W. Price, B. Moore, V. Rangachari, B. Cusack, J. Eriksen, K. Jansen-West, C. Verbeeck, D. Yager, C. Eckman, W. Ye, S. Sagi, B.A. Cottrell, J. Torpey, T.L. Rosenberry, A. Fauq, M.S. Wolfe, B. Schmidt, D.M. Walsh, E.H. Koo, and T.E. Golde Substrate-targeting gamma-secretase modulators Nature 453 2008 925 929
179. L. Richter, L.M. Munter, J. Ness, P.W. Hildebrand, M. Dasari, S. Unterreitmeier, B. Bulic, M. Beyermann, R. Gust, B. Reif, S. Weggen, D. Langosch, and G. Multhaup Amyloid beta 42 peptide (Abeta42)-lowering compounds directly bind to Abeta and interfere with amyloid precursor protein (APP) transmembrane dimerization Proc. Natl. Acad. Sci. U. S. A. 107 2010 14597 14602
180. N. Pozdnyakov, H.E. Murrey, C.J. Crump, M. Pettersson, T.E. Ballard, C.W. Am Ende, K. Ahn, Y.M. Li, K.R. Bales, and D.S. Johnson Gamma-secretase modulator (GSM) photoaffinity probes reveal distinct allosteric binding sites on Presenilin J. Biol. Chem. 288 2013 9710 9720
181. C.J. Crump, B.A. Fish, S.V. Castro, D.M. Chau, N. Gertsik, K. Ahn, C. Stiff, N. Pozdnyakov, K.R. Bales, D.S. Johnson, and Y.M. Li Piperidine acetic acid based gamma-secretase modulators directly bind to Presenilin-1 ACS Chem. Neurosci. 2 2011 705 710
182. Y. Ohki, T. Higo, K. Uemura, N. Shimada, S. Osawa, O. Berezovska, S. Yokoshima, T. Fukuyama, T. Tomita, and T. Iwatsubo Phenylpiperidine-type gamma-secretase modulators target the transmembrane domain 1 of presenilin 1 EMBO J. 30 2011 4815 4824
183. E. Czirr, S. Leuchtenberger, C. Dorner-Ciossek, A. Schneider, M. Jucker, E.H. Koo, C.U. Pietrzik, K. Baumann, and S. Weggen Insensitivity to Abeta42-lowering nonsteroidal anti-inflammatory drugs and gamma-secretase inhibitors is common among aggressive presenilin-1 mutations J. Biol. Chem. 282 2007 24504 24513 (Pubitemid 47347550)
184. R.C. Green, L.S. Schneider, D.A. Amato, A.P. Beelen, G. Wilcock, E.A. Swabb, and K.H. Zavitz Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: a randomized controlled trial JAMA 302 2009 2557 2564
185. T. Kukar, S. Prescott, J.L. Eriksen, V. Holloway, M.P. Murphy, E.H. Koo, T.E. Golde, and M.M. Nicolle Chronic administration of R-flurbiprofen attenuates learning impairments in transgenic amyloid precursor protein mice BMC Neurosci. 8 2007 54
186. S. Sivilia, L. Lorenzini, A. Giuliani, M. Gusciglio, M. Fernandez, V.A. Baldassarro, C. Mangano, L. Ferraro, V. Pietrini, M.F. Baroc, A.R. Viscomi, S. Ottonello, G. Villetti, B.P. Imbimbo, L. Calza, and L. Giardino Multi-target action of the novel anti-Alzheimer compound CHF5074: in vivo study of long term treatment in Tg2576 mice BMC Neurosci. 14 2013 44
187. G. Poli, E. Corda, B. Lucchini, M. Puricelli, P.A. Martino, P. Dall'ara, G. Villetti, S.R. Bareggi, C. Corona, E.V. Costassa, P. Gazzuola, B. Iulini, M. Mazza, P. Acutis, P. Mantegazza, C. Casalone, and B.P. Imbimbo Therapeutic effect of CHF5074, a new gamma-secretase modulator, in a mouse model of scrapie Prion 6 2012 62 72
188. B.P. Imbimbo, E. Frigerio, M. Breda, F. Fiorentini, M. Fernandez, S. Sivilia, L. Giardino, L. Calza, D. Norris, D. Casula, and M. Shenouda Pharmacokinetics and Pharmacodynamics of CHF5074 After Short-term Administration in Healthy Subjects Alzheimer Dis. Assoc. Disord. 2012 (in press)
189. B.D. Moore, P. Chakrabarty, Y. Levites, T.L. Kukar, A.M. Baine, T. Moroni, T.B. Ladd, P. Das, D.W. Dickson, and T.E. Golde Overlapping profiles of Abeta peptides in the Alzheimer's disease and pathological aging brains Alzheimers Res. Ther. 4 2012 18
190. I. Kuperstein, K. Broersen, I. Benilova, J. Rozenski, W. Jonckheere, M. Debulpaep, A. Vandersteen, I. Segers-Nolten, K. Van Der Werf, V. Subramaniam, D. Braeken, G. Callewaert, C. Bartic, R. D'Hooge, I.C. Martins, F. Rousseau, J. Schymkowitz, and B. De Strooper Neurotoxicity of Alzheimer's disease Abeta peptides is induced by small changes in the Abeta42 to Abeta40 ratio EMBO J. 29 2010 3408 3420
191. J. Kim, L. Onstead, S. Randle, R. Price, L. Smithson, C. Zwizinski, D.W. Dickson, T. Golde, and E. McGowan Abeta40 inhibits amyloid deposition in vivo J. Neurosci. 27 2007 627 633 (Pubitemid 46143766)
192. R. Wang, B. Wang, W. He, and H. Zheng Wild-type presenilin 1 protects against Alzheimer disease mutation-induced amyloid pathology J. Biol. Chem. 281 2006 15330 15336 (Pubitemid 43855123)
193. W. He, L. Luistro, D. Carvajal, M. Smith, T. Nevins, X. Yin, J. Cai, B. Higgins, K. Kolinsky, C. Rizzo, K. Packman, D. Heimbrook, and J.F. Boylan High tumor levels of IL6 and IL8 abrogate preclinical efficacy of the gamma-secretase inhibitor, RO4929097 Mol. Oncol. 5 3 2011 292 301
194. L. Luistro, W. He, M. Smith, K. Packman, M. Vilenchik, D. Carvajal, J. Roberts, J. Cai, W. Berkofsky-Fessler, H. Hilton, M. Linn, A. Flohr, R. Jakob-Rotne, H. Jacobsen, K. Glenn, D. Heimbrook, and J.F. Boylan Preclinical profile of a potent gamma-secretase inhibitor targeting notch signaling with in vivo efficacy and pharmacodynamic properties Cancer Res. 69 2009 7672 7680