C Development

Chidambaram Ramachandran, Ph.D

**** ** ***** ****, ********,WA 98029

425-***-**** *******@*****.***

Summary: Drug discovery professional with over 20 years experience focused on target discovery and

validation in leading pharma/biopharma companies. Experience in inflammation/immunology,

Diabetes/Obesity and respiratory diseases therapeutic areas. Effective team leader focused on maximizing

team potential. Developed key tools to interrogate the target and explore the targets potential for

therapeutic development. Mentor of junior scientist’s.

PROFESSIONAL EXPERIENCE

AMGEN, Department of Inflammation, Seattle, WA, 2006-2011

Scientific Director

Responsible for identifying novel targets and initiating drug discovery effort focussed both on small

molecules and large molecules to treat inflammatory and immunologic disorders. These efforts has

resulted in the identification and pursuing of several novel targets (TNF family co-stimulatory molecule

using antibody, several enzymes and GPCR using small molecules and an ion transporter using both

small molecule and an antibody). As a team leader for these programs closely collaborated with

functional areas like protein sciences, Chemistry, HTS, crystallography, molecular modeling, animal

resources, pathology, investigative toxicology, pharmacokinetics and drug metabolism and early

clinical development across multiple sites in North America and Europe.

Mentor of several junior scientists

Member of the inflammation therapeutic area licensing team. Research lead for evaluation of several

external licensing opportunities in inflammation in concert with PKDM, safety and early clinical

development

Established collaboration with academic researchers both in USA and in Europe (Finland and Greece)

to identify novel targets and to obtain earlier insights into the targets that are of interest to us.

MERCK FROSST CENTRE FOR THERAPEUTIC RESEARCH, Montreal, Quebec 1989 – 2005

Department of Biochemistry and Molecular Biology

Senior Research Fellow 1999 – 2005

Research Fellow 1994 – 1998

Senior Research Biochemist 1989 – 1993

Principle investigator of the Protein Tyrosine Phosphatase (PTP) program:

Initiated a research program on tyrosine phosphatases resulting in the identification of PTP-1B as key

negative regulator of insulin signal transduction.

Discovered a novel role of PTP-1B in Obesity. Initiated a drug discovery effort on PTP-1B as a target

for Diabetes and Obesity.

Established and validated screens to identify inhibitors of PTP-1B and appropriate counter screens.

Demonstrated efficacy of the inhibitors in cells and in rodent models of diet-induced obesity/insulin

resistance.

Principle investigator of the proteomics/ biomarker discovery effort:

Initiated a biomarker discovery effort at Merck Frosst and discovered several markers in broncho

alveolar lavage fluid from models of air way hyper activity.

Demonstrated and validated these novel biomarkers as the earliest observable change in the model

system.

Chidambaram Ramachandran, Ph.D. Page 2

Established Isotope coded protein profiling method to quantify proteins in cells/tissues and identified several novel substrates for proteases.

Championed multiplexed biomarker discovery effort resulting in identification of cytokine/chemokines markers for respiratory diseases.

Chair for the following Merck/ external collaborations:

Established collaboration with ISIS Pharmaceuticals for anti sense approach to modulate PTP-1B and insulin-signaling and chaired a joint committee for this collaboration.

Proposed and managed the collaboration with Neogenesis to identify ligands for four Merck targets using a novel affinity selection/ Mass spec technology.

Initiated phosphopeptide profiling with Caprion Pharmaceuticals that led to the discovery of biomarkers for anti-inflammatory drugs.

Supervisory/teaching responsibility:

Directed four to seven immediate reports (M.Sc/Ph.D.).

Guided several B.Sc level co-op students and one Ph.D. student.

Taught phosphorylation and signal transduction courses to graduate students at Concordia University, Montreal.

Member of working groups at Merck Research Laboratories:

Kinase Task Force.

Protein Analysis Working Group.

Molecular Profiling Working Group.

Research Technology and Licensing Working Group.

MAISONNEUVE-ROSEMONT RESEARCH CENTRE, Montreal, Quebec 1987 – 1989

Researcher, Department of Medicine

UNIVERSITY OF CALIFORNIA, Davis, USA 1980 – 1986

Biological Chemistry, School of Medicine

Research Associate / Senior Post-doctoral fellow 1982 – 1986

Juvenile Diabetes Foundation Fellow 1980 – 1982

AUSTRALIAN NATIONAL UNIVERSITY, Canberra, Australia 1977 – 1980

Graduate student, Tutor, Biochemistry

LADY HARDINGE MEDICAL COLLEGE, New Delhi, India 1975 – 1976

Demonstrator, Biochemistry

EDUCATION

Ph.D. Biochemistry, Australian National University, Canberra, Australia 1980

M.Sc. Biochemistry, JIPMER, University of Madras, Madras, India 1975

B.Sc. Chemistry, Madurai University, Madurai, India 1972

Chidambaram Ramachandran, Ph.D. Page 3

Publications

1. Bygrave, F.L., Ramachandran, C. and Smith, R.L. "On the mechanism by which inorganic phosphate stimulates mitochondrial calcium transport." FEBS Letts., 83, 155-158, 1977.

2. Bygrave, F.L., Ramachandran, C. and Robertson, R.N. "Interaction of tributyltin with mitochondrial calcium transport system of rat liver." Arch. Biochem. Biophys., 188, 301-307, 1978.

3. Ramachandran, C. and Bygrave, F.L. "Calcium ion cycling in rat liver mitochondria." Biochem. J., 174, 613-620, 1979.

4. Bygrave, F.L., Heaney, T.P. and Ramachandran, C. "Submitochondrial location of Ruthenium Red-sensitive mitochondrial calcium ion transport and evidence for its enrichment in a specific population of rat liver mitochondria." Biochem. J., 174, 1011-1019, 1979.

5. Ramachandran, C. and Bygrave, F.L. "Ruthenium Red-sensitive and Ruthenium Red-insensitive release of calcium by mitochondria isolated from rat liver and rat heart." Cell Calcium, 2, 411-423, 1981.

6. Ramachandran, C., Angelos, K.L. and Walsh, D.A. "Cyclic AMP-dependent and cyclic AMP-independent antagonism of insulin-stimulated cardiac glycogen synthase." J. Biol. Chem., 257, 1448-1457, 1982.

7. Ramachandran, C., Angelos, K.L., Sivaramakrishnan, S. and Walsh, D.A.. "Regulation of cardiac glycogen synthase." Feb. Proc., 42, 9-13, 1983.

8. Ramachandran, C., Angelos, K.L. and Walsh, D.A. "Hormonal regulation of the phosphorylation of cardiac glycogen synthase." J. Biol. Chem., 258, 133**-*****, 1983.

9. Ramachandran, C., Yau, P., Bradbury, E.M., Shyamala, G., Yasuda, H. and Walsh, D.A. "Phosphorylation of high-mobility group proteins by the calcium-phospholipid-dependent protein kinase and the cyclic AMP-dependent protein kinase." J. Biol. Chem., 259, 134**-*****, 1984.

10. Ramachandran, C., Picket-Gies, C., Goris, J., Waelkens, E., Merlevede, W. and Walsh, D.A. "Regulation of phosphorylase kinase by homologous and heterologous subunit interactions." Advances in Protein phosphatases, 2, 355-374, 1985.

11. Ramachandran, C., Goris, J., Waelkens, E., Merlevede, W. and Walsh, D.A. "The interrelationship between cAMP--subunit phosphorylation in the regulation of phosphorylase kinase activity." J. Biol. Chem., 262, 3210-3218, 1987.

12. Angelos, K.L., Ramachandran, C. and Walsh, D.A. "Subunit phosphorylation and activation of phosphorylase kinase in perfused rat hearts." J. Biol. Chem., 262, 3219-3226, 1987.

13. Cawley, K.C., Ramachandran, C., Gorin, F.A. and Walsh, D.A. "Nucleotide sequence of cDNA encoding the catalytic subunit of phosphorylase kinase from rat soleus muscle." Nucl. Acid Res., 16, 2355-2356, 1988.

14. Ramachandran, C., Catelli, M.G., Schneider, W. and Shyamala, G. "Estrogenic regulation of uterine 90 kilodalton heat shock protein." Endocrinology, 123, 956-961, 1988.

15. Ramachandran, C. and Brunette, M.G. "The renal Na+/Ca2+ exchange system is located exclusively in the distal tubule." Biochem. J., 257, 259-264, 1989.

16. Catelli, M.G., Ramachandran, C., Gauthier, Y., Legagneux, V., Quelard, C., Baulieu, E.E. and Shyamala, G. "Developmental regulation of murine mammary-gland 90 KDa heat-shock proteins." Biochem. J., 258, 895-901, 1989.

17. Brunette, M.G., Leclerc, M., Ramachandran, C., Lafond, J. and Lajeunesse, D. "Influence of insulin on phosphate uptake by brush border membranes from human placenta." Molecular and Cellular Endocrinology, 63, 57-65, 1989.

18. Brunette, M.G., Mailloux, J., Chan, M. and Ramachandran, C. "Characterization of the high and low affinity components of the renal Ca2+-Mg2+ ATPase." Canadian Journal of Physiology & Pharmacology, 68, 718-726, 1990.

Chidambaram Ramachandran, Ph.D. Page 4

19. Schneider, W., Ramachandran, C., Satyaswaroop, P.G. and Shyamala, G. "Murine progesterone receptor exists predominantly as the 83-kilodalton 'A' form." Journal of Steroid Biochemistry & Molecular Biology, 38, 285-291, 1991.

20. Ramachandran, C., Chan, M. and Brunette, M.G. "Characterization of ATP-dependent Ca2+ transport in the basolateral vesicles from proximal and distal tubules of the rabbit kidney." Biochem. Cell. Biol., 69, 109-114, 1991.

21. Ramachandran, C., Aebersold, R., Tonks, N.K. and Pot, D.A. "Sequential dephosphorylation of a multiply phosphorylated insulin receptor peptide by protein tyrosine phosphatases." Biochemistry, 31, 4232-4238, 1992.

22. Lee, J.-H., Maeda, S., Angelos, K.L., Kamita, S.G., Ramachandran, C. and Walsh, D.A. "Analysis -subunit of skeletal muscle phosphorylase kinase expressed using a baculovirus system." Biochemistry, 31, 106**-*****, 1992.

23. Bastien, L., Ramachandran, C., Liu, S. and Adam, M. "Cloning, expression and mutational analysis of SH-PTP2, human protein-tyrosine phosphatase." Biochem. Biophys. Res. Commun., 196, 124-133, 1993.

24. Townley, R., Shen, S.-H., Banville, D. and Ramachandran, C. "Inhibition of the activity of protein tyrosine phosphatase 1C by its SH2 domains." Biochemistry, 32, 134**-*****, 1993.

25. Chauret, N., Li, C., Ducharme, Y., Trimble, L.A., Yergey, J.A., Ramachandran, C. and Nicoll-Griffith, D.A. "In vitro and in vivo biotransformations of the naphthalenic lignan lactone 5-lipoxygenase inhibitor, L-702,539." Drug Metabolism and Disposition, 23, 65-71, 1995.

26. Huyer, G., Li, Z.M., Adam, M., Huckle, W.R. and Ramachandran, C. "Direct determination of the sequence recognition requirements of SH2 domains of SH-PTP2." Biochemistry, 34, 1040-1049, 1995.

27. Schmidt, A., Rutledge, S.J., Endo, N., Opas, E., Tanaka, H., Wesolowski, G., Leu, C.T., Huang, Z., Ramachandran, C., Rodan, S.B. and Rodan, G.A. "Protein tyrosine phosphatase activity regulates osteclast formation and function: Inhibition by alendronate." Proc. Natl. Acad. Sci., 93, 3068-3073, 1996.

28. Huyer, G., Liu, S., Kelly, J., Moffat, J., Payette, P., Kennedy, B., Tsaprailis, G., Gresser, M.J. and Ramachandran, C. "Mechanism of inhibition of protein-tyrosine phosphatases by vanadate and pervanadate." J. Biol. Chem., 272, 843-851, 1997.

29. Skorey, K., Ly, O.H.D., Kelly, J., Hammond, H., Ramachandran, C., Huang, Z., Gresser, M.J. and Wang, Q. "How does alendronate inhibit protein-tyrosine phosphatases?" J. Biol. Chem., 272, 224**-*****, 1997.

30. Wang, Q., Janzen, N., Ramachandran, C. and Jirik, F. "Mechanism of inhibition of protein-tyrosine phosphatases by disodium aurothiomalate." Biochem. Pharmacol., 54, 703-711, 1997.

31. Huyer, G., Kelly, J., Moffat, J., Zamboni, R., Jia, Z., Gresser, M. J. and Ramachandran, C. "Affinity selection from peptide libraries to determine substrate specificity of protein tyrosine phosphatases." Anal. Biochem., 258, 19-30, 1998.

32. Huyer, G. and Ramachandran, C. "Specificity of N-terminal domain of SH2 domain of SHP-2 is modified by a single point mutation." Biochemistry, 37, 2741-2747, 1998.

33. Desmarais, S., Jia, Z. and Ramachandran, C. "Inhibition of protein tyrosine phosphatases PTP1B and CD45 by sulfotyrosyl peptides." Arch. Biochem. Biophys., 354, 225-231, 1998.

34. Wang, Q., Ramachandran, C., Dinaut, N., Huang, Z., Taylor, S. "Naphthalene Bis[a,a-Difluoromethylenephosphonates]naphthalene as Potent Inhibitors of Protein Tyrosine Phosphatases." Bioorg. Med. Chem. Lett., 8, 345-350., 1998.

35. Taylor, S., Kotoris, C., Dinaut, A. N., Wang, Q., Ramachandran, C. and Huang, Z. "Potent Non-peptidyl inhibitors of Protein Tyrosine Phosphatase 1B." Bio. Med. Chem., 6 , 1457-1468, 1998.

Chidambaram Ramachandran, Ph.D. Page 5

36. Desmarais, S., Friesen, R., Zamboni, R. and Ramachandran, C. "[Difluoro(phosphono)methyl]phenylalanine-containing peptide inhibitiors of protein tyrosine phosphatases." Biochem. J., 337, 219-223, 1999.

37. Elchebly, M., Payette, P., Michaliszyn, E., Cromlish, W., Collins, S., Loy, A. L., Normandin, D., Cheng, A., Chan, C-C., Ramachandran, C., Gresser, M.J., Tremblay, M. L. and Kennedy, B. P. "Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase 1B gene." Science, 283,1544-1548, 1999.

38. Gamble, T.N., Ramachandran, C. and Bateman, K.V. "Phosphopeptide Isomer Separation Using Capillary Zone Electrophoresis for the Study of Protein Kinases and Phosphatases." Anal. Chem., 71, 3469-3476, 1999.

39. Cuncic, C., Detich,N., Ethier, D., Tracey, A.S., Gresser, M.J. and Ramachandran, C. "Why Vanadate Is Not Effective in Increasing Phosphotyrosine Levels in All Cells? Modulation by Redox State." J. Biol. & Inorganic Chem., 4 , 354-359, 1999.

40. Wang, Q., Scheigetz, J., Gilbert, M., Snider, J. and Ramachandran, C. "Fluorescein Monophosphates As Fluorogenic Substrates for Protein Tyrosine Phosphatases." Biochim. Biophys. Acta, 1431, 14-23, 1999.

41. Huang, Z., Wang, Q., Hoa, L., Gorvindarajan, A., Scheigetz, J., Zamboni, R., Desmarais, S. Ramachandran. C. "3,6-Fluorescein diphosphate: a sensitive fluorogenic and chromogenic substrate for protein tyrosine phosphatases". J. Biomolecular Screen, 4, 327-333. 1999.

42. Cuncic, C., Desmarais, S., Detich, N., Tracey, A.S., Gresser, M.J. and Ramachandran, C. "Bis (N,N-dimethylhydroxyamido)hydroxooxovanadate Inhibition of Protein Tyrosine Phosphatase Activity in Intact Cells. Comparison with Vanadate." Biochem. Pharmacol., 58, 1859-1867, 1999.

43. Nxumalo, F., Tracey, A.S., Detich, N., Gresser, M.J. Ramachandran, C. "A new class of insulin- mimetic compounds." ACS Symposium series 711 Vanadium compounds, pages 259-269, 1999.

44. Ducret, A., Desponts, C., Desmarais, S., Gresser, M.J. and Ramachandran, C "A general method for the rapid characterization of tyrosine-phosphorylated proteins by mini two-dimensional gel electrophoresis." Electrophoresis, 21, 2196-2208, 2000.

45. Waddleton, D., Ramachandran, C. and Wang, Q.P "Development of a method for Evaluating Protein Tyrosine Phosphatase CD45 inhibitors using Jurkat cell membrane." Anal. Biochem., 285, 58-63, 2000.

46. Kennedy, B.P. and Ramachandran, C. "Protein tyrosine phosphatase-1B in diabetes." Biochem Pharmacol., 60, 877-883, 2000.

47. Asante-Appiah, E., Ball, K., Bateman, K., Skorey, K., Friesen, R., Desponts, C., Payette, P., Bayly, C., Zamboni, R., Scapin, G., Ramachandran, C. and Brian P. Kennedy. "The YRD Motif is a Major Determinant of Substrate and Inhibitor Specificity in T-cell Protein-Tyrosine Phosphatase." J. Biol.Chem., 276, 260**-*****, 2001.

48. Skorey, K.I., Kennedy, B.P., Friesen, R.F. and Ramachandran, C. "Development of a Robust Scintillation Proximity Assay for Protein Tyrosine Phosphatase 1B using the Catalytically Inactive (C215S) Mutant." Anal. Biochem., 291, 269-278, 2001.

49. Jia, Z., Ye, Q.,. Nicole Dinaut, A., Wang, Q., Waddleton, D., Payette, P., Ramachandran, C., Kennedy, B., Hum, G. and Taylor, S.D. "Structure of Protein Tyrosine Phosphatase 1B in Complex with Inhibitors Bearing Two Phosphotyrosine Mimetics." J. Med. Chem ,44, 4584-4594, 2001.

50. Asante-Appiah, E., Patel, S., Dufresne, C., Roy, P., Wang, Q., Patel, V., Friesen, R.W., Ramachandran, C., Becker, J.W., Leblanc, Y., Kennedy, B.P. and Scapin, G. "The Structure of PTP-1B in Complex with a Peptide Inhibitor Reveals an Alternative Binding Mode for Bisphosphonates" Biochemistry 41, 9043-9051, 2002.

51. Wang, Q., Scheigetz, J., Roy, B., Ramachandran, C. and Gresser, M.J. " Novel Caged Fluorescein diphosphates as photoactivatable substrates for protein tyrosine phosphatases " Biochim. Biophys. Acta 1601, 19-28, 2002.

Chidambaram Ramachandran, Ph.D. Page 6

52. Waddleton, D., Ramachandran, C. and Wang, Q. " Development of a time resolved fluorescent assay for measuring tyrosine phosphorylated proteins in cells " Anal. Biochem 309, 150-157, 2002.

53. Ramachandran, C. and Kennedy, B.P. "Protein Tyrosine Phosphatase 1B: A Novel target for Type 2 Diabetes and Obesity" Curr. Top. Med. Chem. 3, 749-757, 2003.

54. Scapin, G., Patel, S.B., Becker, J.W., Wang, Q., Desponts, C., Waddleton, D., Skorey, K., Bayly,C., Therien, M., Gauthier, J.Y., Li, C.S., Lau, C.K., Ramachandran, C., Kennedy, B.P. and Asante-Appiah, E. " The structural basis for the selectivity of Benzotriazole inhibitors of PTP1B” Biochemistry 42, 114**-*****, 2003

55. Dufresne, C., Roy, P., Wang, Z., Asante-Appiah, E., Cromlish, W., Boie, Y., Forghani, F., Desmarais, S., Wang, Q., Skorey, K., Waddleton, D., Ramachandran, C., Kennedy, B.P., Xu, L., Gordon, R., Chan, C.C. and Leblanc, Y. "The development of potent non-peptidic PTP-1B inhibitors" Bioorganic & Medicinal Chemistry Letters 14, 1039-1042, 2004

56. Lau, C.K., Bayly, C.I., Gauthier, J.Y., Li, C.S., Therien, M., Asante-Appiah, E., Cromlish, W., Boie, Y., Forghani, F., Desmarais, S., Wang, Q., Skorey, K., Waddleton, D., Payette, P., Ramachandran, C., Kennedy, B.P. and Scapin, G. "Structure based design of a series of potent and selective non peptidic PTP-1B inhibitors" Bioorganic & Medicinal Chemistry Letters 14, 1043-1048, 2004

57. Wang, Q., Dubé, D., Friesen, R.F., LeRiche, T.G., Bateman, K.B., Trimble, L., Sanghara, J., Pollex, R., Ramachandran, C., Gresser, M.J. and Huang, Z. "Catalytic Inactivation of Protein Tyrosine Phosphatase CD45 and Protein Tyrosine Phosphatase 1B by Polyaromatic Quinones " Biochemistry 43, 4294-4303, 2004

58. Thérien, M., Skorey, K., Zamboni, R., Li, C.S., Lau, C.K., LeRiche, T., Truong, V.L., Waddleton, D. and Ramachandran, C. " Synthesis of a novel peptidic photoaffinity probe for the PTP-1B enzyme " Bioorganic & Medicinal Chemistry Letters 14, 2319-2322, 2004

59. Therien AG, Bernier V, Weicker S, Tawa P, Falgueyret JP, Mathieu MC, Honsberger J, Pomerleau V, Robichaud A, Stocco R, Dufresne L, Houshyar H, Lafleur J, Ramachandran C, O'Neill GP, Slipetz D, Tan CM " Adenovirus IL-13-induced airway disease in mice: a corticosteroid-resistant model of severe asthma " Am J Respir Cell Mol Biol. 39, 26-35 2008

60. Hétu PO, Ouellet M, Falgueyret JP, Ramachandran C, Robichaud J, Zamboni R, Riendeau D. "Photo-crosslinking of proteins in intact cells reveals a dimeric structure of cyclooxygenase-2 and an inhibitor-sensitive oligomeric structure of microsomal prostaglandin E2 synthase-1" Arch Biochem Biophys. 477, 155-162, 2008

Patents

1. Desmarais, S., Friesen, R., Gresser, M., Kennedy, B., Nicholson, D., Ramachandran, C., Skorey, K. and Ford-Hutchinson, A. "Analysis of ligand binding to cysteine-containing enzymes using cysteine replacement mutants and phosphono(difluoromethyl)phenylalanine-containing ligands." PCT Int. Appl. 63 pp. WO 9820156 A1 980514 CAN 129:38122; AN 1998:324912.

2. Kennedy, B., Payette, P., Gresser, M., Ramachandran, C. and Tremblay, M. " Protein Tyrosine Phosphatase-1B (PTP-1B) deficient mice and uses thereof. " PCT Int. Appl WO 00/06712

3. Ramachandran, C., Therien, M., Lau, C. K. and Zamboni, R." PTP1B Photo probe” PCT Int. Appl. 52 pp. WO2005056582 A1

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