MARK S. SHEARMAN, Ph.D
Executive Director, Neuroscience Drug Discovery

Dr. Mark Shearman obtained his Bachelor of Science degree in 1983 from the University of Bristol (UK). In 1987, he was awarded a Doctorate of Philosophy from the Department of Biochemistry at the University of Nottingham, England. Dr. Shearman was a Max-Planck Gessellschaft Research Fellow under Professor Axel Ulrich at the Max-Planck Institute for Biochemistry and Psychiatry in Munich, Germany, and a Royal Society/Japan Society for the Promotion of Science Research Fellow under Professor Yasutomi Nishizuka in the Department of Biochemistry at Kobe School of Medicine in Kobe, Japan.

In 1992, Dr. Shearman joined Merck Sharp & Dohme Research Laboratories in the United Kingdom as a Senior Research Biochemist. Since then, he has held numerous leadership roles in the company’s Alzheimer’s Disease Therapeutic Area Group where he most recently was the Senior Director, Department of Cellular & Molecular Neuroscience. He was presented the Merck Leadership Award in 2005 for his contributions in this area. He joined MRL-Boston in 2006 as Senior Director, Neuroscience Drug Discovery.

Dr. Shearman has authored more than 90 research publications and has been a guest speaker at more than 50 international scientific meetings.

Selected Key Publications, 2003 – Present
Nadin, A., Owens, A.P., Castro, J.L., Harrison, T. & Shearman, M.S.
Synthesis and gamma-secretase activity of APP substrate-based hydroxyethylene dipeptide isosteres.
Bioorg. Med. Chem. Lett 2003 Jan 6; 13(1): 37-41.

Grimm, H., Beher, D., Lichtenthaler, S.F., Shearman, M.S., Beyreuther, K. & Hartmann, T.
Gamma-secretase cleavage site specificity differs for intracellular and secretory amyloid-beta peptides.
J. Biol. Chem. 2003 Apr 11; 278(15) 13007-85.

Churcher, I., Williams, S., Kerrad, S., Harrison, T., Castro, J.L., Shearman, M.S., Lewis, H.D., Clarke, E.E., Wrigley, J.D.J., Beher, D., Tang, Y.S. & Liu, W.
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 June 5; 46(12): 2275-2278.

Lewis, H.D., Perez-Revuelta, B.I., Nadin, A., Neduvelil, J.G., Harrison, T., Pollack, S.J. & Shearman, M.S.
Catalytic site-directed gamma-secretase complex inhibitors do not discriminate pharmacologically between Notch S3 and beta-APP cleavages.
Biochemistry 2003 June 24; 42(24): 7580-7586.

Beher, D., Fricker, M., Nadin, A., Clarke, E.E., Wrigley, J.D.J.,   Li, Y-M., Culvenor, J.G., Masters, C.L., Harrison, T. & Shearman, M.S.
In vitro characterization of the presenilin-dependent gamma-secretase complex using a novel affinity ligand.
Biochemistry 2003 July 15; 42(27): 8133-8142.

Schroeter, E.H., Ilagan, M.X.G., Brunkan, A.L., Hecimovic, S., Li, Y., Xu, M., Lewis, H.D., Saxena, M.T., De Strooper, B., Coonrod, A., Tomita, T., Iwatsubo, T., Moore, C.L., Shearman, M.S., Goate, A., Wolfe, M.S. & Kopan, R.
A presenilin dimer at the core of gamma-secretase activity: insights from parallel analysis of Notch 1 and APP proteolysis.
Proc. Natl. Acad. Sci. USA   2003 Oct 28; 100(22): 13075-13080.

Lewis, H.D., Beher, D., Smith, D., Hewson, L., Cookson, N., Reynolds, D.S., Dawson, G.R., Van der Ploeg, L.H.T., Qian, S., Rosahl, T.R., Kalaria, R.N. & Shearman, M.S.
Novel aspects of deposition dynamics and A beta composition in transgenic models of Alzheimer's disease.
Neurobiol. Aging 2004 Oct; 25(9): 1175-1185.

Brandon, N.J., Handford, E.J., Schurov, I., Rain, J-C., Pelling, M., Duran-Jimeniz, B., Camargo, M., Oliver, K.R., Beher, D., Shearman, M.S. & Whiting, P.
Disrupted in Schizophrenia 1 (DISC1) and Nudel form a neurodevelopmentally regulated protein complex: implications for schizophrenia and other major neurological disorders.  
Mol. Cell. Neurosci. 2004 Jan; 25(1): 42-55.

Wrigley, J.D.J., Nunn, E.J., Nyabi, O., Clarke, E.E., Hunt, P., Nadin, A., De Strooper, B., Shearman, M.S. & Beher, D.
Conserved residues within the putative active site of gamma-secretase differentially influence enzyme activity and inhibitor binding.  
J. Neurochem. 2004 Sept; 90(6): 1312-1320.

Beher, D., Clarke, E.E., Wrigley, J.D.J., Maryin, A.C.L., Nadin, A., Churcher, I. & Shearman, M.S.
Selected non-steroidal anti-inflammatory drugs and derivatives thereof   target gamma-secretase at a novel site–evidence for an allosteric mechanism.  
J. Biol. Chem. 2004 Oct 15; 279(42): 43419-43426.

Liu, Y., Yang, L., Conde-Knape, K., Beher, D., Shearman, M.S. & Shachter, N.
Fatty acids increase presenilin-1 levels and gamma-secretase activity in PSwt-1 cells.  
J. Lipid Res. 2004 Sept 16; 45: 2368-2376.

Capell, A., Beher, D., Prokop, S., Steiner, H., Kaether, C., Shearman, M.S. & Haass, C.
Gamma-secretase complex assembly within the early secretory pathway.  
J. Biol. Chem. 2005 Feb 25; 280(8): 6471-6478.

Lewis, S.J., Smith, A.L., Neduvelil, J.G., Stevenson, G.I., Lindon, M.J., Jones, A.B., Shearman, M.S., Beher, D., Clarke, E.E., Best, J.D., Peachey, J.E., Harrison, T. & Castro, J.L.
A novel series of potent gamma-secretase inhibitors based on a benzobicyclo[4.2.1]nonane core.
Bioorg Med Chem Lett. 2005 Jan 17; 15(2): 373-378.

Wrigley, J.D.J., Schurov, I., Nunn, E.J., Martin, A.C.L., Clarke, E.E., Ellis, S., Bonnert, T.P., Shearman, M.S. & Beher, D.
Functional overexpression of gamma-secretase reveals protease independent trafficking functions and a critical role of lipids for protease activity.  
J. Biol. Chem. 2005 Apr 1; 280(13): 12523-12535.

Best, J.D, Jay, M.Y., Out, F., Ma, J., Nadin, A., Ellis, S., Lewis, H.D., Pattison, C., Reilly, M., Harrison, T., Shearman, M.S., Williamson, T.L. & Atack, J.R.
Quantitative measurement of changes in amyloid-beta (40) in the rat brain and CSF following treatment with the gamma-secretase inhibitor, N2-[(2S)-2-(3,5-Difluorophenyl)-2-hydroxyethanoyl]-N1-[(7S)-5-methyl-6-oxo-6,7-dihydro-5Hdibenzo[b,d]azepin-7-yl]-L-alaninamide (LY-411575)
J. Pharmacol Exp Ther. 2005 May; 313(2): 902-908.

Brandon, N.J., Schurov, I., Camargo, M., Handford, E.J., Duran-Jimeniz, B., Hunt, P., Millar, J.K., Porteous, D.J., Shearman, M.S. & Whiting, P.
Subcellular targeting of DISC1 is dependent on a domain independent from the Nudel binding site.  
Mol. Cell. Neurosci. 2005 April; 28(4): 613-624.

Teall, M., Oakley, P., Harrison, T., Shaw, D., Kay, E., Elliott, J., Gerhard, U., Castro, J.L., Shearman, M.S., Ball, R.G. & Tsou, N.N.
Aryl sulphones: a new class of gamma-secretase inhibitors.
Bioorg. Medchem Lett. 2005 May 16; 15(10): 2685-2688.

Brundan, A.L., Martinez, M., Wang, E.S., Beher, D., Shearman, M.S. & Goate, A.M.
Two domains within the first putative transmembrane domain of presenilin 1 differentially influence presenilinase and gamma-secretase activity.
J. Neurochem. 2005 Sept; 94(5): 1315-1328.

Capell, A., Beher, D., Prokop, S., Steiner, H., Kaether, C., Shearman, M. S., and Haass, C.
Gamma-secretase complex assembly within the early secretory pathway.
J. Biol. Chem. 2005 Feb 25; 280(8): 6471-8.

Sparey, T., Beher, D., Best, J., Biba, M., Castro, J. L., Clarke, E., Hannam, J., Harrison, T., Lewis, H., Madin, A., Shearman, M.S., Sohal, B., Tsou, N., Welch, C., and Wrigley, J.
Cyclic sulfamide gamma-secretase inhibitors.
Bioorg. Med. Chem. Lett. 2005 Oct 1; 15(19): 4212-4216.

Churcher, I., Beher, D., Best, J.D., Castro, J.L., Clarke, E.E., Gentry, A., Harrison, T., Hitzel, L., Kay, E., Kerrad, S., Lewis, H.D., Morentin-Gutierrez, P., Mortishire-Smith, R., Oakley, P.J., Reilly, M., Shaw, D.E., Shearman, M.S., Teall, M.R., Williams, S. & Wrigley, J.D.
4-Substituted cyclohexyl sulfones as potent, orally active gamma-secretase inhibitors.
Bioorg. Med. Chem. Lett. 2006 Jan 15; 16(2): 280-284.