Gamma secretase inhibitors: a patent review (2013 - 2015)

References

• Henry W, Querfurth MD, Frank M. LaFerla. Mechanisms of disease Alzheimer’s disease. New Engl J Med. 2010;362:329–344.
   PubMed Web of Science ®Google Scholar
• Korczyn AD. The amyloid cascade hypothesis. Alzheimers Dement. 2008;4:176–178.
   PubMed Web of Science ®Google Scholar
• Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science. 2002;297:353–356.
   PubMed Web of Science ®Google Scholar
• Huang Y, Mucke L. Alzheimer mechanisms and therapeutic strategies. Cell. 2012;148:1204–1222.
   PubMed Web of Science ®Google Scholar
• Citron M. Alzheimer’s disease: strategies for disease modification. Nat Rev Drug Discov. 2010;9:387–398.
   PubMed Web of Science ®Google Scholar
• Strooper BD, Vassar R, Golde T. The secretases: enzymes with therapeutic potential in Alzheimer disease. Nat Rev Neurol. 2010;6:99–107.
   PubMed Web of Science ®Google Scholar
• Helena Niño JER-B, Xerardo G-M, Francisco -P-P. Review of synthesis, assay, and prediction of β and γ-secretase inhibitors. Curr Top Med Chem. 2012;12:828–844.
   PubMed Web of Science ®Google Scholar
• Sambamurti K, Greig NH, Utsuki T, et al. Targets for AD treatment: conflicting messages from gamma-secretase inhibitors. J Neurochem. 2011;117:359–374.
   PubMed Web of Science ®Google Scholar
• Singh R, Barman A, Prabhakar R. Computational insights into aspartyl protease activity of presenilin 1 (PS1) generating Alzheimer amyloid β-peptides (Aβ40 and Aβ42). J Phys Chem B. 2009;113:2990–2999.
   PubMed Web of Science ®Google Scholar
• Walter J, Kaether C, Steiner H, et al. The cell biology of Alzheimer’s disease: uncovering the secrets of secretases. Curr Opin Neurobio. 2001;11:585–590.
   PubMed Web of Science ®Google Scholar
• Bai XC, Yan C, Yang G, et al. An atomic structure of human gamma-secretase. Nature. 2015;525:212–217.
   PubMed Web of Science ®Google Scholar
• Xie T, Yan C, Zhou R, et al. Crystal structure of the gamma-secretase component nicastrin. P Natl Acad Sci USA. 2014;111:13349–13354.
   PubMed Web of Science ®Google Scholar
• Sun L, Zhao L, Yang G, et al. Structural basis of human gamma-secretase assembly. P Natl Acad Sci USA. 2015;112:6003–6008.
   PubMed Web of Science ®Google Scholar
• Lu P, Bai XC, Ma D, et al. Three-dimensional structure of human gamma-secretase. Nature. 2014;512:166–170.
   PubMed Web of Science ®Google Scholar
• Strooper BD. Aph-1, Pen-2, and nicastrin with presenilin generate an active γ-secretase complex. Neuron. 2003;38:9–12.
   PubMed Web of Science ®Google Scholar
• Wolfe MS, Kopan R. Intramembrane proteolysis: theme and variations. Science. 2004;305:1119–1123.
   PubMed Web of Science ®Google Scholar
• Takasugi N, Takahashi Y, Morohashi Y, et al. The mechanism of gamma-secretase activities through high molecular weight complex formation of presenilins is conserved in Drosophila melanogaster and mammals. J Biol Chem. 2002;277:50198–50205.
   PubMed Web of Science ®Google Scholar
• Strooper BD, Saftig P, Craessaerts K, et al. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature. 1998;391:387–390.
   PubMed Web of Science ®Google Scholar
• Ahn K, Shelton CC, Tian Y, et al. Activation and intrinsic gamma-secretase activity of presenilin 1. P Natl Acad Sci USA. 2010;107:21435–21440.
   PubMed Web of Science ®Google Scholar
• Sannerud R, Esselens C, Ejsmont P, et al. Restricted location of PSEN2/γ-secretase determines substrate specificity and generates an intracellular Aβ pool. Cell. 2016;166:1–16.
   PubMed Web of Science ®Google Scholar
• Herreman A, Van Gassen G, Bentahir M, et al. γ-Secretase activity requires the presenilin-dependent trafficking of nicastrin through the Golgi apparatus but not its complex glycosylation. J Cell Sci. 2003;116:1127–1136.
   PubMed Web of Science ®Google Scholar
• Steiner H. Uncovering γ-secretase. Curr Alzheimer Res. 2004;1:175–181.
   PubMedGoogle Scholar
• Shah S, Lee SF, Tabuchi K, et al. Nicastrin functions as a gamma secretase-substrate receptor. Cell. 2005;122:435–447.
   PubMed Web of Science ®Google Scholar
• Takasugi N, Tomita T, Hayashi I, et al. The role of presenilin cofactors in the λ-secretase complex. Nature. 2003;422:438–441.
   PubMed Web of Science ®Google Scholar
• Goutte C, Tsunozaki M, Hale VA, et al. APH-1 is a multipass membrane protein essential for the Notch signaling pathway in Caenorhabditis elegans embryos. P Natl Acad Sci USA. 2002;99:775–779.
   PubMed Web of Science ®Google Scholar
• Periz G, Fortini ME. Functional reconstitution of gamma-secretase through coordinated expression of presenilin, nicastrin, Aph-1, and Pen-2. J Neurosci Res. 2004;77:309–322.
   PubMed Web of Science ®Google Scholar
• Shirotani K, Edbauer D, Prokop S, et al. Identification of distinct γ-secretase complexes with different APH-1 variants. J Biol Chem. 2004;279:41340–41345.
   PubMed Web of Science ®Google Scholar
• Serneels L, Van Biervliet J, Craessaerts K, et al. γ-Secretase heterogeneity in the Aph1 subunit: relevance for Alzheimer’s disease. Science. 2009;324:639–642.
   PubMed Web of Science ®Google Scholar
• Crystal AS, Morais VA, Pierson TC, et al. Membrane topology of gamma-secretase component PEN-2. J Biol Chem. 2003;278:20117–20123.
   PubMed Web of Science ®Google Scholar
• Mitani Y, Yarimizu J, Saita K, et al. Differential effects between γ-secretase inhibitors and modulators on cognitive function in amyloid precursor protein-transgenic and nontransgenic mice. J Neurosci. 2012;32:2037–2050.
   PubMed Web of Science ®Google Scholar
• Haapasalo A, Kovacs DM. The many substrates of presenilin/gamma-secretase. J Alzheimers Dise. 2011;25:3–28.
   PubMed Web of Science ®Google Scholar
• Kopan R, Ilagan MX. The canonical Notch signaling pathway: unfolding the activation mechanism. Cell. 2009;137:216–233.
   PubMed Web of Science ®Google Scholar
• Searfoss GH, Jordan WH, Calligaro DO, et al. Adipsin, a biomarker of gastrointestinal toxicity mediated by a functional gamma-secretase inhibitor. J Biol Chem. 2003;278:46107–46116.
   PubMed Web of Science ®Google Scholar
• Wong GT, Manfra D, Poulet FM, et al. Chronic treatment with the gammasecretase inhibitor LY-411,575 inhibits beta-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation. J Biol Chem. 2004;279:12876–12882.
   PubMed Web of Science ®Google Scholar
• Schor NF. What the halted phase III gamma-secretase inhibitor trial may (or may not) be telling us. Ann Neurol. 2011;69:237–239.
   PubMed Web of Science ®Google Scholar
• Yuan X, Wu H, Xu H, et al. Notch signaling: an emerging therapeutic target for cancer treatment. Cancer Lett. 2015;369:20–27.
   PubMed Web of Science ®Google Scholar
• Purow B. Notch inhibition as a promising new approach to cancer therapy. Adv Exp Med and Biol. 2012;727:305–319.
   PubMed Web of Science ®Google Scholar
• Klafki H-W, Swoboda DA,R, Paganetti PA, et al. The carboxyl termini of β-amyloid peptides 1–40 and 1–42 are generated by distinct γ-Secretase activities. J Biol Chem. 1996;271:28655–28659.
   PubMed Web of Science ®Google Scholar
• Park H, Kim HS, Choi H-J, et al. Preparation of N-acetyl-L-leucyl-L-leucyl-L-norleucinal (ALLN) derivatives for preventing or treating malaria. WO2014084471A1. 2014.
   Google Scholar
• Jeffrey N, Higaki SC, Bryant CM, et al. A combinatorial approach to the identification of dipeptide aldehyde inhibitors of â-Amyloid production. J Med Chem. 1999;42:3889–3898.
   PubMed Web of Science ®Google Scholar
• Wallace OB, Smith DW, Deshpande MS, et al. Inhibitors of Aβ production: solid-phase synthesis and SAR of α-hydroxycarbonyl derivatives. Bioorg Med Chem Let. 2003;13:1203–1206.
   PubMed Web of Science ®Google Scholar
• Michael S. W, Citron M, Thekla S, et al. A substrate-based difluoro ketone selectively inhibits Alzheimer’s γ-secretase activity. J Med Chem. 1998;41:6–9.
   PubMed Web of Science ®Google Scholar
• Michael S. W, Xia W, Moore CL, et al. Peptidomimetic probes and molecular modeling suggest that Alzheimer’s γ-secretase is an intramembrane-cleaving aspartyl protease. Biochemistry-US. 1999;38:4720–4727.
   PubMed Web of Science ®Google Scholar
• Moore CL, Leatherwood DD, Diehl TS, et al. Difluoro ketone peptidomimetics suggest a large S1 pocket for Alzheimer’s γ-secretase: implications for inhibitor design. J Med Chem. 2000;43:3434–3442.
   PubMed Web of Science ®Google Scholar
• Shearman MS, Beher D, Clarke EE, et al. L-685,458, an aspartyl protease transition state mimic, is a potent inhibitor of amyloid β-protein precursor γ-secretase activity. Biochemistry-US. 2000;39:8698–8704.
   PubMed Web of Science ®Google Scholar
• Castro Pineiro JL, Harrison T, Hunt PA, et al. Preparation of peptide derivatives as γ-secretase inhibitors. WO2001053255A1. 2001.
   Google Scholar
• Esler WP, Das C, Wolfe MS. Probing pockets S2-S4ʹ of the gamma-secretase active site with (hydroxyethyl)urea peptidomimetics. Bioorg Med Chem Let. 2004;14:1935–1938.
   PubMed Web of Science ®Google Scholar
• Bakshi P, Wolfe MS. Stereochemical analysis of (hydroxyethyl)urea peptidomimetic inhibitors of γ-secretase. J Med Chem. 2004;47:6485–6489.
   PubMed Web of Science ®Google Scholar
• Robertson ES, Lan K γ-secretase inhibitors for the treatment of herpesvirus infection. US20120183508A1; 2012
   Google Scholar
• Chittaranjan Das OB, Diehl TS, Genet C, et al. Designed helical peptides inhibit an intramembrane protease. J Am Chem Soc. 2003;125:11794–11795.
   PubMed Web of Science ®Google Scholar
• Bihel F, Das C, Bowman MJ, et al. Discovery of a subnanomolar helical D-tridecapeptide inhibitor of gamma-secretase. J Med Chem. 2004;47:3931–3933.
   PubMed Web of Science ®Google Scholar
• Kornilova AY, Bihel F, Das C, et al. The initial substrate-binding site of gamma-secretase is located on presenilin near the active site. P Natl Acad Sci USA. 2005;102:3230–3235.
   PubMed Web of Science ®Google Scholar
• Wolfe MS. Helical peptidomimetics with enhanced activity. WO2005118634A2. 2005
   Google Scholar
• Feng S, Zhu S, Ruan J, et al. Combination therapy of RY10-4 with the γ-secretase inhibitor DAPT shows promise in treating HER2-amplified breast cancer. Oncotarget. 2015;7:4142–4154.
   Web of Science ®Google Scholar
• Kalantari E, Saeidi H, Kia NS, et al. Effect of DAPT, a gamma secretase inhibitor, on tumor angiogenesis in control mice. Adv Biomed Res. 2013;2:83.
   PubMedGoogle Scholar
• Wang J. Compositions comprising farnesyl transferase inhibitor (FTI) and a gamma-secretase inhibitor (GSI) for targeting glioblastomas cells. US8853274B1. 2014.
   Google Scholar
• Huw D, BIPrR L, Nadin A, et al. Catalytic site-directed γ-secretase complex inhibitors do not discriminate pharmacologically between Notch S3 and β-APP cleavages. Biochemistry-US. 2003;42:7580–7586.
   PubMed Web of Science ®Google Scholar
• Hyde LA, McHugh NA, Chen J, et al. Studies to investigate the in vivo therapeutic window of the gamma-secretase inhibitor N2-[(2S)-2-(3,5-difluoroph-enyl)-2-hydroxyethanoyl]-N1-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-L-alaninamide (LY411,575) in the CRND8 mouse. J Pharmacol Exp The. 2006;319:1133–1143.
   PubMed Web of Science ®Google Scholar
• Koenig TM, Audia JE, Mitchell D, et al. Preparation of lactam derivative useful for inhibiting β-amyloid peptide release and/or its synthesis. WO2002040451A2; 2002.
   Google Scholar
• Doody RS, Raman R, Farlow M, et al. A phase 3 trial of semagacestat for treatment of Alzheimer’s disease. New Engl J Med. 2013;369:341–350.
   PubMed Web of Science ®Google Scholar
• Siemers ER, Dean RA, Friedrich S, et al. Safety, tolerability, and effects on plasma and cerebrospinal fluid amyloid-beta after inhibition of gamma-secretase. Clin Neuropharmac. 2007;30:317–325.
   PubMed Web of Science ®Google Scholar
• Brodney MA, Coffman KJ, Kleinman EF, et al. Preparation of amino acid imidazolylamides for treatment of neurological disorders. WO2007034326A2; 2007.
   Google Scholar
• Wei P, Walls M, Qiu M, et al. Evaluation of selective gamma-secretase inhibitor PF-03084014 for its antitumor efficacy and gastrointestinal safety to guide optimal clinical trial design. Mol Cancer Ther. 2010;9:1618–1628.
   PubMed Web of Science ®Google Scholar
• Lopez-Guerra M, Xargay-Torrent S, Rosich L, et al. The gamma-secretase inhibitor PF-03084014 combined with fludarabine antagonizes migration, invasion and angiogenesis in NOTCH1-mutated CLL cells. Leukemia. 2015;29:96–106.
   PubMed Web of Science ®Google Scholar
• Churcher I, Ashton K, Butcher JW, et al. A new series of potent benzodiazepine gamma-secretase inhibitors. Bioorg Med Chem Let. 2003;13:179–183.
   PubMed Web of Science ®Google Scholar
• Castro Pineiro JL, Churcher I, Guiblin AR, et al. Benzodiazepine derivatives as amyloid precursor protein modulators. WO2001090084A1; 2001
   Google Scholar
• Owens AP, Nadin A, Talbot AC, et al. High affinity, bioavailable 3-amino-1,4-benzodiazepine-based gamma-secretase inhibitors. Bioorg Med Chem Let. 2003;13:4143–4145.
   PubMed Web of Science ®Google Scholar
• Churcher I, Williams S, Kerrad S, et al. 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. 2003;46:2275–2278.
   PubMed Web of Science ®Google Scholar
• Castro Pineiro JL, Churcher I, Guiblin AR, et al. Benzodiazepine derivatives as APP modulators. US7105509B2; 2006
   Google Scholar
• Sehgelmeble F, Janson J, Ray C, et al. Sulfonimidamides as sulfonamides bioisosteres: rational evaluation through synthetic, in vitro, and in vivo studies with gamma-secretase inhibitors. ChemMedChem. 2012;7:396–399.
   PubMed Web of Science ®Google Scholar
• Kreft AF, Cole DC, Woller KR, et al. Heterocyclic sulfonamides inhibitors of beta amyloid production. WO02057252A2; 2002
   Google Scholar
• Cole DC, Diamantidis G, Galante RJ, et al. Fluoro-and-trifluoroalkyles containing heterocyclic sulfonamides inhibitors of beta amyloide production and derivatives thereof. WO2004092155A1; 2004
   Google Scholar
• Zhang M, Porte A, Diamantidis G, et al. Asymmetric synthesis of novel alpha-amino acids with beta-branched side chains. Bioorg Med Chem Let. 2007;17:2401–2403.
   PubMed Web of Science ®Google Scholar
• Martone RL, Zhou H, Atchison K, et al. Begacestat (GSI-953): a novel, selective thiophene sulfonamide inhibitor of amyloid precursor protein gamma-secretase for the treatment of Alzheimer’s disease. J Pharmacol Exp The. 2009;331:598–608.
   PubMed Web of Science ®Google Scholar
• Parker MF, McElhone KE, Mate RA, et al. Preparation of α-(N-sulfonamido)acetamides as β-amyloid inhibitors. WO2003053912A1; 2003
   Google Scholar
• Gillman KW, Starrett JE Jr., Parker MF, et al. Discovery and evaluation of BMS-708163, a potent, selective and orally bioavailable gamma-secretase inhibitor. ACS Med Chem Lett. 2010;1:120–124.
   PubMed Web of Science ®Google Scholar
• Cf A, Rc D, Je M Jr, et al. Pharmacodynamics of selective inhibition of gamma-secretase by avagacestat. J Pharmacol Exp The. 2013;344:686–695.
   PubMed Web of Science ®Google Scholar
• Strooper DB. Lessons from a failed gamma-secretase Alzheimer trial. Cell. 2014 6;159:721–726.
   PubMed Web of Science ®Google Scholar
• Coric V, Stephen Salloway CH. van Dyck, et al. Targeting prodromal Alzheimer disease with avagacestat: a randomized clinical trial. JAMA Neurol. 2015;72:1324–1333.
   Google Scholar
• Coric V, Van Dyck CH, Salloway S, et al. Safety and tolerability of the gamma-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease. Arch Neurol-Chicag. 2012;69:1430–1440.
   PubMed Web of Science ®Google Scholar
• Hoffmann-Emery F, Jakob-Roetne R Process for the preparation of dibenzo[b,d]azepin-6-one derivative. WO2008145525A2,A3. 2008.
   Google Scholar
• Olsauskas-Kuprys R, Zlobin A, Osipo C. Gamma secretase inhibitors of Notch signaling. Oncotargets Ther. 2013;6:943–955.
   PubMed Web of Science ®Google Scholar
• Tolcher AW, Messersmith WA, Mikulski SM, et al. Phase I study of RO4929097, a gamma secretase inhibitor of Notch signaling, in patients with refractory metastatic or locally advanced solid tumors. J Clin Onco. 2012;30:2348–2353.
   PubMed Web of Science ®Google Scholar
• Lee SM, Moon J, Redman BG, et al. Phase 2 study of RO4929097, a gamma-secretase inhibitor, in metastatic melanoma: SWOG 0933. Cancer. 2014;121:432–440.
   PubMed Web of Science ®Google Scholar
• De Jesus-Acosta A, Laheru D, Maitra A, et al. A phase II study of the gamma secretase inhibitor RO4929097 in patients with previously treated metastatic pancreatic adenocarcinoma. Invest New Drugs. 2014;32:739–745.
   PubMed Web of Science ®Google Scholar
• Huynh C, Poliseno L, Segura MF, et al. The novel gamma secretase inhibitor RO4929097 reduces the tumor initiating potential of melanoma. Plos One. 2011;6:e25264.
   PubMed Web of Science ®Google Scholar
• Hazel C, Gj A, Danahay H. IL-13-induced changes in the goblet cell density of human bronchial epithelial cell cultures: MAP kinase and phosphatidylinositol 3-kinase regulation. Am J Physiol-Lung C. 2003;285:L730–L39.
   PubMed Web of Science ®Google Scholar
• Kuperman DA, Huang X, Koth LL, et al. Direct effects of interleukin-13 on epithelial cells cause airway hyperreactivity and mucus overproduction in asthma. Nat Med. 2002;8:885–889.
   PubMed Web of Science ®Google Scholar
• Laoukili J, Perret E, Willems T, et al. IL-13 alters mucociliary differentiation and ciliary beating of human respiratory epithelial cells. J Clin Invest. 2001;108:1817–1824.
   PubMed Web of Science ®Google Scholar
• Novartis AG, Switz. Gamma secretase inhibitors for treating respiratory diseases. EP2932966A1; 2015
   Google Scholar
• Garcia-Alloza M, Subramanian M, Thyssen D, et al. Existing plaques and neuritic abnormalities in APP:PS1 mice are not affected by administration of the gamma-secretase inhibitor LY-411575. Mol Neurodegener. 2009;4:19.
   PubMed Web of Science ®Google Scholar
• Edge A, Okano H, Fujioka M, et al. Treating hearing loss using certain gamma secretase inhibitors. WO2014039781A1; 2014
   Google Scholar
• Jtcada C. Regeneration of sensory hair cells after acoustic trauma. Science. 1988;240:1772–1774.
   PubMed Web of Science ®Google Scholar
• Julie Adam AM, Le Roux I, Eddison M, et al. Cell fate choices and the expression of Notch, Delta and Serrate homologues in the chick inner ear: parallels with Drosophila sense-organ development. Development. 1998;125:4645–4654.
   PubMed Web of Science ®Google Scholar
• Doetzlhofer A, Basch ML, Ohyama T, et al. Hey2 regulation by FGF provides a Notch-independent mechanism for maintaining pillar cell fate in the organ of Corti. Dev Cell. 2009;16:58–69.
   PubMed Web of Science ®Google Scholar
• Hartman BH, Basak O, Nelson BR, et al. Bermingham-McDonogh O. Reh TA. Hes5 Expression in the postnatal and adult mouse inner ear and the drug-damaged cochlea. JARO-J Assoc Res Oto. 2009;10:321–340.
   Google Scholar
• Churcher I, Harrison T, Kerrad S, et al. Cyclohexyliques sulfones as gamma-secretase inhibitors. WO2004031139A1; 2004
   Google Scholar
• Best JD, Smith DW, Reilly MA, et al. The novel gamma secretase inhibitor N-[cis-4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexyl]-1,1,1-trifluor-omethanesulfonamide (MRK-560) reduces amyloid plaque deposition without evidence of notch-related pathology in the Tg2576 mouse. J Pharmacol Exp The. 2007;320:552–558.
   PubMed Web of Science ®Google Scholar
• Lee J, Song L, Terracina G, et al. Identification of presenilin 1-selective gamma-secretase inhibitors with reconstituted gamma-secretase complexes. Biochemistry. 2011;50:4973–4980.
   PubMed Web of Science ®Google Scholar
• Teall M, Oakley P, Harrison T, et al. Aryl sulfones: a new class of gamma-secretase inhibitors. Bioorg Med Chem Let. 2005;15:2685–2688.
   PubMed Web of Science ®Google Scholar
• Churcher I, Beher D, Best JD, et al. 4-substituted cyclohexyl sulfones as potent, orally active gamma-secretase inhibitors. Bioorg Med Chem Let. 2006;16:280–284.
   PubMed Web of Science ®Google Scholar
• Jelley RA, Elliott J, Gibson KR, et al. 3-Substituted gem-cyclohexane sulfone-based gamma-secretase inhibitors for Alzheimer’s disease: conformational analysis and biological activity. Bioorg Med Chem Let. 2006;16:3839–3842.
   PubMed Web of Science ®Google Scholar
• Pissarnitski D, Zhao Z Spirocyclic sulfones as gamma secretase inhibitors. WO2014085211A2; 2014
   Google Scholar
• Zhao Z, Pissarnitski DA, Josien HB, et al. Discovery of a novel, potent spirocyclic series of gamma-secretase inhibitors. J Med Chem. 2015;58:8806–8817.
   PubMed Web of Science ®Google Scholar
• Li T, Wen H, Brayton C, et al. Moderate reduction of γ-secretase attenuates amyloid burden and limits mechanism-based liabilities. J Neurosci. 2007;27:10849–10859.
   PubMed Web of Science ®Google Scholar
• Boylan JF, Mikulski S Method for administration of a gamma secretase inhibitor for treating cancer. US20140357620A1; 2014.
   Google Scholar
• Wu W-L, Burnett DA, assignee. Gamma secretase inhibitors. WO2013036464A1; 2013.
   Google Scholar