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Mark Shearman

Research Profile

Chemicals & Drugs

Disorders

Alzheimer's Disease

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Mouse

Anatomy

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Physiology

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Administration, Oral

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Publications

TOP 3
Jacquelynn J Cook; Kristin R Wildsmith; David B Gilberto; Marie A Holahan; Gene G Kinney; Parker D Mathers; Maria S Michener; Eric A Price; Mark S Shearman; Adam J Simon; Jennifer X Wang; Guoxin Wu; Kevin E Yarasheski; Randall Bateman
Acute gamma-secretase inhibition of nonhuman primate CNS shifts amyloid precursor protein (APP) metabolism from amyloid-beta production to alternative APP fragments without amyloid-beta rebound.
Linda E Keown; Ian Collins; Laura C Cooper; Timothy Harrison; Andrew Madin; Jayesh Mistry; Michael Reilly; Mohamed Shaimi; Christopher J Welch; Earl E Clarke; Huw D Lewis; Jonathan D J Wrigley; Jonathan D Best; Fraser Murray; Mark S Shearman
Novel orally bioavailable gamma-secretase inhibitors with excellent in vivo activity.
Tim Sparey; Earl E Clarke; Joanne Hannam; Timothy Harrison; Andrew Madin; Mark S Shearman; Bindi Sohal
Sulfonamide derivatives of bridgehead substituted bicyclo[4.2.1]nonanes as gamma-secretase inhibitors.

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All Publications

2010: Jacquelynn J Cook; Kristin R Wildsmith; David B Gilberto; Marie A Holahan; Gene G Kinney; Parker D Mathers; Maria S Michener; Eric A Price; Mark S Shearman; Adam J Simon; Jennifer X Wang; Guoxin Wu; Kevin E Yarasheski; Randall Bateman
Acute gamma-secretase inhibition of nonhuman primate CNS shifts amyloid precursor protein (APP) metabolism from amyloid-beta production to alternative APP fragments without amyloid-beta rebound.
The Journal of neuroscience : the official journal of the Society for Neuroscience 2010;30(19):6743-50.
2009: Linda E Keown; Ian Collins; Laura C Cooper; Timothy Harrison; Andrew Madin; Jayesh Mistry; Michael Reilly; Mohamed Shaimi; Christopher J Welch; Earl E Clarke; Huw D Lewis; Jonathan D J Wrigley; Jonathan D Best; Fraser Murray; Mark S Shearman
Novel orally bioavailable gamma-secretase inhibitors with excellent in vivo activity.
Journal of medicinal chemistry 2009;52(11):3441-4.
2008: Tim Sparey; Earl E Clarke; Joanne Hannam; Timothy Harrison; Andrew Madin; Mark S Shearman; Bindi Sohal
Sulfonamide derivatives of bridgehead substituted bicyclo[4.2.1]nonanes as gamma-secretase inhibitors.
Bioorganic & medicinal chemistry letters 2008;18(1):375-9.
2007: Guy R Seabrook; William Ray; Mark S Shearman; Michael Hutton
Beyond amyloid: the next generation of Alzheimer's disease therapeutics.
Molecular interventions 2007;7(5):261-70.
2007: Huw D Lewis; Matthew Leveridge; Peter R Strack; Christine D Haldon; Jennifer O'Neil; Hellen Kim; Andrew Madin; Joanne C Hannam; A Thomas Look; Nancy Kohl; Giulio F Draetta; Timothy Harrison; Julie A Kerby; Mark S Shearman; Dirk Beher
Apoptosis in T cell acute lymphoblastic leukemia cells after cell cycle arrest induced by pharmacological inhibition of notch signaling.
Chemistry & biology 2007;14(2):209-19.
2007: Jonathan D Best; David W Smith; Michael A Reilly; Ruth O'Donnell; Huw D Lewis; Semantha Ellis; Neil Wilkie; Thomas W Rosahl; Philippe Laroque; Christine Boussiquet-Leroux; Ian Churcher; John R Atack; Timothy Harrison; Mark S Shearman
The novel gamma secretase inhibitor N-[cis-4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexyl]-1,1,1-trifluoromethanesulfonamide (MRK-560) reduces amyloid plaque deposition without evidence of notch-related pathology in the Tg2576 mouse.
The Journal of pharmacology and experimental therapeutics 2007;320(2):552-8.
2006: John Majercak; William Ray; Amy S Espeseth; Adam Simon; Xiao-Ping Shi; Carrie Wolffe; Krista Getty; Shane Marine; Erica Stec; Marc Ferrer; Berta Strulovici; Steven Bartz; Adam Gates; Min Xu; Qian Huang; Lei Ma; Paul J Shughrue; Julja Burchard; Dennis Colussi; Beth L Pietrak; Jason Kahana; Dirk Beher; Thomas W Rosahl; Mark S Shearman; Daria J Hazuda; Alan B Sachs; Kenneth S Koblan; Guy R Seabrook; David J Stone
LRRTM3 promotes processing of amyloid-precursor protein by BACE1 and is a positional candidate gene for late-onset Alzheimer's disease.
Proceedings of the National Academy of Sciences of the United States of America 2006;103(47):17967-72.
2006: Julian L Goggi; Huw D Lewis; Joanie Mok; Timothy Harrison; Mark S Shearman; John R Atack; Jonathan D Best
A comparative assessment of gamma-secretase activity in transgenic and non-transgenic rodent brain.
Journal of neuroscience methods 2006;157(2):246-52.
2006: Earl E Clarke; Ian Churcher; Semantha Ellis; Jonathan D J Wrigley; Huw D Lewis; Timothy Harrison; Mark S Shearman; Dirk Beher
Intra- or intercomplex binding to the gamma-secretase enzyme. A model to differentiate inhibitor classes.
The Journal of biological chemistry 2006;281(42):31279-89.
2006: Richard A Jelley; Jason Elliott; Karl R Gibson; Timothy Harrison; Dirk Beher; Earl E Clarke; Huw D Lewis; Mark S Shearman; Jonathan D J Wrigley
3-Substituted gem-cyclohexane sulfone based gamma-secretase inhibitors for Alzheimer's disease: conformational analysis and biological activity.
Bioorganic & medicinal chemistry letters 2006;16(14):3839-42.
2006: Duncan Shaw; Jonathan Best; Kevin Dinnell; Alan Nadin; Mark S Shearman; Christine Pattison; James Peachey; Michael Reilly; Brian Williams; Jonathan D J Wrigley; Timothy Harrison
3,4-Fused cyclohexyl sulfones as gamma-secretase inhibitors.
Bioorganic & medicinal chemistry letters 2006;16(11):3073-7.
2006: Jonathan D Best; Mark T Jay; Otu Franklin; Ian Churcher; Michael Reilly; Pablo Morentin-Gutierrez; Christine Pattison; Timothy Harrison; Mark S Shearman; John R Atack
In vivo characterization of Abeta(40) changes in brain and cerebrospinal fluid using the novel gamma-secretase inhibitor N-[cis-4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexyl]-1,1,1-trifluoromethanesulfonamide (MRK-560) in the rat.
The Journal of pharmacology and experimental therapeutics 2006;317(2):786-90.
2006: Nicholas Stock; Benito Munoz; Jonathan D J Wrigley; Mark S Shearman; Dirk Beher; James E Peachey; Toni L Williamson; Gretchen Bain; Weichao Chen; Xiaohui Jiang; Rene St-Jacques; Peppi Prasit
The geminal dimethyl analogue of Flurbiprofen as a novel Abeta42 inhibitor and potential Alzheimer's disease modifying agent.
Bioorganic & medicinal chemistry letters 2006;16(8):2219-23.
2006: H Lewis; Dirk Beher; Natalie Cookson; A Oakley; Margaret A Piggott; C M Morris; Evelyn Jaros; Robert H Perry; Paul Ince; Rose Anne Kenny; Clive G Ballard; Mark S Shearman; Rajesh N. Kalaria
Quantification of Alzheimer pathology in ageing and dementia: age-related accumulation of amyloid-beta(42) peptide in vascular dementia.
Neuropathology and applied neurobiology 2006;32(2):103-18.
2006: Ian Churcher; Dirk Beher; Jonathan D Best; José L Castro; Earl E Clarke; Amy Gentry; Timothy Harrison; Laure Hitzel; Euan Kay; Sonia Kerrad; Huw D Lewis; Pablo Morentin-Gutierrez; Russell Mortishire-Smith; Paul J Oakley; Michael Reilly; Duncan E Shaw; Mark S Shearman; Martin R Teall; Susie Williams; Jonathan D J Wrigley
4-substituted cyclohexyl sulfones as potent, orally active gamma-secretase inhibitors.
Bioorganic & medicinal chemistry letters 2006;16(2):280-4.
2006: Jun Wang; Dirk Beher; Andrew C Nyborg; Mark S Shearman; todd golde; Alison Goate
C-terminal PAL motif of presenilin and presenilin homologues required for normal active site conformation.
Journal of neurochemistry 2006;96(1):218-27.
2005: Tim Sparey; Dirk Beher; Jonathan Best; Mirlinda Biba; José L Castro; Earl E Clarke; Joanne Hannam; Timothy Harrison; Huw Lewis; Andrew Madin; Mark S Shearman; Bindi Sohal; Nancy N Tsou; Christopher Welch; Jonathan D J Wrigley
Cyclic sulfamide gamma-secretase inhibitors.
Bioorganic & medicinal chemistry letters 2005;15(19):4212-6.
2005: Anne L Brunkan; Maribel Martinez; Jun Wang; Emily S Walker; Dirk Beher; Mark S Shearman; Alison Goate
Two domains within the first putative transmembrane domain of presenilin 1 differentially influence presenilinase and gamma-secretase activity.
Journal of neurochemistry 2005;94(5):1315-28.
2005: Sarah Grimwood; J Hogg; Mark T Jay; A M Lad; Virginia M-Y Lee; Fraser Murray; James E Peachey; T Townend; M Vithlani; Dirk Beher; Mark S Shearman; Peter H Hutson
Determination of guinea-pig cortical gamma-secretase activity ex vivo following the systemic administration of a gamma-secretase inhibitor.
Neuropharmacology 2005;48(7):1002-11.
2005: Martin R Teall; Paul Oakley; Timothy Harrison; Duncan Shaw; Euan Kay; Jason Elliott; Ute Gerhard; José L Castro; Mark S Shearman; Richard G Ball; Nancy N Tsou
Aryl sulfones: a new class of gamma-secretase inhibitors.
Bioorganic & medicinal chemistry letters 2005;15(10):2685-8.
2005: Jonathan D Best; Mark T Jay; Otu Franklin; Jerome Ma; Alan Nadin; Semantha Ellis; Huw D Lewis; Christine Pattison; Michael Reilly; Timothy Harrison; Mark S Shearman; Toni L Williamson; John R Atack
Quantitative measurement of changes in amyloid-beta(40) in the rat brain and cerebrospinal fluid following treatment with the gamma-secretase inhibitor LY-411575 [N2-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N1-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-L-alaninamide].
The Journal of pharmacology and experimental therapeutics 2005;313(2):902-8.
2005: Nicholas J Brandon; Irina Schurov; L Miguel Camargo; EJ Handford; B Duran-Jimeniz; P Hunt; J Kirsty Millar; David J Porteous; Mark S Shearman; Paul J Whiting
Subcellular targeting of DISC1 is dependent on a domain independent from the Nudel binding site.
Molecular and cellular neurosciences 2005;28(4):613-24.
2005: Jonathan D J Wrigley; Irina Schurov; Emma J Nunn; Agnes C L Martin; Earl E Clarke; Semantha Ellis; Timothy P Bonnert; Mark S Shearman; Dirk Beher
Functional overexpression of gamma-secretase reveals protease-independent trafficking functions and a critical role of lipids for protease activity.
The Journal of biological chemistry 2005;280(13):12523-35.
2005: Anja Capell; Dirk Beher; Stefan Prokop; Harald Steiner; Christoph Kaether; Mark S Shearman; Christian Haass
Gamma-secretase complex assembly within the early secretory pathway.
The Journal of biological chemistry 2005;280(8):6471-8.
2005: Stephen J Lewis; Adrian L Smith; Joseph G Neduvelil; Graeme I Stevenson; Matthew J Lindon; A Brian Jones; Mark S Shearman; Dirk Beher; Earl E Clarke; Jonathan D Best; James E Peachey; Timothy Harrison; José L Castro
A novel series of potent gamma-secretase inhibitors based on a benzobicyclo[4.2.1]nonane core.
Bioorganic & medicinal chemistry letters 2005;15(2):373-8.
2004: Yanzhu Liu; Lin Yang; Karin Conde-Knape; Dirk Beher; Mark S Shearman; Neil S Shachter
Fatty acids increase presenilin-1 levels and [gamma]-secretase activity in PSwt-1 cells.
Journal of lipid research 2004;45(12):2368-76.
2004: Dirk Beher; Earl E Clarke; Jonathan D J Wrigley; Agnes C L Martin; Alan Nadin; Ian Churcher; Mark S Shearman
Selected non-steroidal anti-inflammatory drugs and their derivatives target gamma-secretase at a novel site. Evidence for an allosteric mechanism.
The Journal of biological chemistry 2004;279(42):43419-26.
2004: Huw D Lewis; Dirk Beher; David Smith; Louise Hewson; Natalie Cookson; David S Reynolds; Gerard R Dawson; Michael Jiang; Lex H T Van Der Ploeg; Su Qian; Thomas W Rosahl; Rajesh N. Kalaria; Mark S Shearman
Novel aspects of accumulation dynamics and A beta composition in transgenic models of AD.
Neurobiology of aging 2004;25(9):1175-85.
2004: Jonathan D J Wrigley; Emma J Nunn; Omar Nyabi; Earl E Clarke; Peter Hunt; Alan Nadin; Bart De Strooper; Mark S Shearman; Dirk Beher
Conserved residues within the putative active site of gamma-secretase differentially influence enzyme activity and inhibitor binding.
Journal of neurochemistry 2004;90(6):1312-20.
2004: Nicholas J Brandon; EJ Handford; Irina Schurov; Jean-Christophe Rain; M Pelling; B Duran-Jimeniz; L Miguel Camargo; K R Oliver; Dirk Beher; Mark S Shearman; Paul J Whiting
Disrupted in Schizophrenia 1 and Nudel form a neurodevelopmentally regulated protein complex: implications for schizophrenia and other major neurological disorders.
Molecular and cellular neurosciences 2004;25(1):42-55.
2003: Eric H Schroeter; Ma Xenia G Ilagan; Anne L Brunkan; Silva Hecimovic; Yueming Li; Min Xu; Huw D Lewis; Meera T Saxena; Bart De Strooper; Archie Coonrod; Taisuke Tomita; Takeshi Iwatsubo; Chad L Moore; Alison Goate; Michael S Wolfe; Mark S Shearman; Raphael Kopan
A presenilin dimer at the core of the gamma-secretase enzyme: insights from parallel analysis of Notch 1 and APP proteolysis.
Proceedings of the National Academy of Sciences of the United States of America 2003;100(22):13075-80.
2003: Dirk Beher; Michael Fricker; Alan Nadin; Earl E Clarke; Jonathan D J Wrigley; Yueming Li; Janetta G Culvenor; Colin L Masters; Timothy Harrison; Mark S Shearman
In vitro characterization of the presenilin-dependent gamma-secretase complex using a novel affinity ligand.
Biochemistry 2003;42(27):8133-42.
2003: Huw D Lewis; Blanca I Pérez-Revuelta; Alan Nadin; Joseph G Neduvelil; Timothy Harrison; Scott J Pollack; Mark S Shearman
Catalytic site-directed gamma-secretase complex inhibitors do not discriminate pharmacologically between Notch S3 and beta-APP cleavages.
Biochemistry 2003;42(24):7580-6.
2003: Ian Churcher; Susie Williams; Sonia Kerrad; Timothy Harrison; José L Castro; Mark S Shearman; Huw D Lewis; Earl E Clarke; Jonathan D J Wrigley; Dirk Beher; Yui S Tang; Wensheng Liu
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.
Journal of medicinal chemistry 2003;46(12):2275-8.
2003: Heike S Grimm; Dirk Beher; Stefan F Lichtenthaler; Mark S Shearman; Konrad Beyreuther; Tobias Hartmann
gamma-Secretase cleavage site specificity differs for intracellular and secretory amyloid beta.
The Journal of biological chemistry 2003;278(15):13077-85.
2003: Alan Nadin; Andrew P Owens; José L Castro; Timothy Harrison; Mark S Shearman
Synthesis and gamma-secretase activity of APP substrate-based hydroxyethylene dipeptide isosteres.
Bioorganic & medicinal chemistry letters 2003;13(1):37-41.
2002: Min Xu; Ming-Tain Lai; Qian Huang; Jillian DiMuzio-Mower; José L Castro; Timothy Harrison; Alan Nadin; Joseph G Neduvelil; Mark S Shearman; Jules A Shafer; Stephen J Gardell; Yueming Li
gamma-Secretase: characterization and implication for Alzheimer disease therapy.
Neurobiology of aging 2002;23(6):1023-30.
2002: Dirk Beher; Mark S Shearman
Gamma-secretase inhibition.
Biochemical Society transactions 2002;30(4):534-7.
2002: Dirk Beher; Jonathan D J Wrigley; Andrew P Owens; Mark S Shearman
Generation of C-terminally truncated amyloid-beta peptides is dependent on gamma-secretase activity.
Journal of neurochemistry 2002;82(3):563-75.
2002: Andreas Papassotiropoulos; Huw D Lewis; Metin Bagli; Frank Jessen; Ursula Ptok; Andrea Schulte; Mark S Shearman; Reinhard Heun
Cerebrospinal fluid levels of beta-amyloid(42) in patients with Alzheimer's disease are related to the exon 2 polymorphism of the cathepsin D gene.
Neuroreport 2002;13(10):1291-4.
2002: Robin A Morton; Frederick M Kuenzi; Stephen Fitzjohn; Thomas W Rosahl; David Smith; Hui Zheng; Mark S Shearman; Graham Collingridge; Guy R Seabrook
Impairment in hippocampal long-term potentiation in mice under-expressing the Alzheimer's disease related gene presenilin-1.
Neuroscience letters 2002;319(1):37-40.
2002: Stefan F Lichtenthaler; Dirk Beher; Heike S Grimm; Rong Wang; Mark S Shearman; Colin L Masters; Konrad Beyreuther
The intramembrane cleavage site of the amyloid precursor protein depends on the length of its transmembrane domain.
Proceedings of the National Academy of Sciences of the United States of America 2002;99(3):1365-70.
2001: Dirk Beher; Jonathan D J Wrigley; Alan Nadin; Geneviève Evin; Colin L Masters; Timothy Harrison; José L Castro; Mark S Shearman
Pharmacological knock-down of the presenilin 1 heterodimer by a novel gamma -secretase inhibitor: implications for presenilin biology.
The Journal of biological chemistry 2001;276(48):45394-402.
2001: Janelle Nunan; Mark S Shearman; F Checler; Roberto Cappai; Geneviève Evin; Konrad Beyreuther; Colin L Masters; David Small
The C-terminal fragment of the Alzheimer's disease amyloid protein precursor is degraded by a proteasome-dependent mechanism distinct from gamma-secretase.
European journal of biochemistry / FEBS 2001;268(20):5329-36.
2001: Stephen Fitzjohn; Robin A Morton; Frederick M Kuenzi; Thomas W Rosahl; Mark S Shearman; H Lewis; D Smith; David S Reynolds; Ceri H Davies; Graham Collingridge; Guy R Seabrook
Age-related impairment of synaptic transmission but normal long-term potentiation in transgenic mice that overexpress the human APP695SWE mutant form of amyloid precursor protein.
The Journal of neuroscience : the official journal of the Society for Neuroscience 2001;21(13):4691-8.
2000: E E Clarke; Mark S Shearman
Quantitation of amyloid-beta peptides in biological milieu using a novel homogeneous time-resolved fluorescence (HTRF) assay.
Journal of neuroscience methods 2000;102(1):61-8.
2000: Mark S Shearman; Dirk Beher; Earl E Clarke; Huw D Lewis; Timothy Harrison; P Hunt; Alan Nadin; Adrian L Smith; G Stevenson; José L Castro
L-685,458, an aspartyl protease transition state mimic, is a potent inhibitor of amyloid beta-protein precursor gamma-secretase activity.
Biochemistry 2000;39(30):8698-704.
2000: Yueming Li; Min Xu; Ming-Tain Lai; Qian Huang; José L Castro; Jillian DiMuzio-Mower; Timothy Harrison; C Lellis; Alan Nadin; Joseph G Neduvelil; Robert B Register; Mohinder K Sardana; Mark S Shearman; Adrian L Smith; Xiao-Ping Shi; KC Yin; Jules A Shafer; Stephen J Gardell
Photoactivated gamma-secretase inhibitors directed to the active site covalently label presenilin 1.
Nature 2000;405(6787):689-94.
1999: François G Gervais; D Xu; George S Robertson; John P Vaillancourt; Y Zhu; J Huang; A LeBlanc; D Smith; M Rigby; Mark S Shearman; E E Clarke; Hui Zheng; L H Van Der Ploeg; Salvatore C Ruffolo; Nancy A Thornberry; Steven Xanthoudakis; Robert Zamboni; Sophie Roy; Donald W Nicholson
Involvement of caspases in proteolytic cleavage of Alzheimer's amyloid-beta precursor protein and amyloidogenic A beta peptide formation.
Cell 1999;97(3):395-406.