Partner 10

Short name: CNRS

Principal Investigator: Laurent MEIJER, Station Biologique de Roscoff

Laurent Meijer was trained at the University of Lille where he obtained his PhD in 1978 (Dir. Maurice DURCHON). This was followed by a post-doctoral stay at the Hopkins Marine Station (the Stanford University marine laboratory), in David EPEL's laboratory. His work was then focused on the changes in protein phosphorylation, which occur as Urechis oocytes are fertilized and re-enter M phase and cell divisions. He then obtained a researcher position at the CNRS and joined Pierre GUERRIER's group at the "Station Biologique de Roscoff", where he investigated the role of protein phosphorylation during the G2/M transition of a very convenient model, the starfish oocyte. In 1983, he obtained the title of "Docteur d'Etat de l'Université de Paris". Two years later, he joined Edwin KREBS' (Nobel Prize laureate 1992) and Bennett SHAPIRO's groups at the University of Washington, Department of Biochemistry. There he extensively characterized the so-called M-phase specific Histone H1 kinase, a kinase activated in all cells as they enter the M phase of the cell division cycle. In 1988, his group, collaborating with David BEACH in Cold Spring Harbor, identified the catalytic subunit of this kinase as CDC2, now better known under CDK1. A year later, with Tim HUNT (Nobel Prize laureate 2001) he identified the associated regulatory subunit as cyclin B, and in 1990, demonstrated that the CDK1/cyclin B complex was activated by subtle changes in phosphorylation of both subunits. As this fundamental research was carried out, LM became interested in using these essential cell cycle regulators as molecular targets for the identification of new anti-mitotic agents of potential therapeutic interest. In 1991, the CDK1 screening method was described, followed by the cdc25 screening method in 1992. These simple assays have since been widely used by many pharmaceutical companies in their efforts for detecting new anti-tumor agents. LM's group also participated to the race through the identification, characterization and optimization of a few families of chemical inhibitors of cyclin-dependent kinases: olomoucine, roscovitine, purvalanol, paullones, indirubins, hymenialdisine, meridianins, aloisines, etc. These inhibitors have generated considerable interest in various fields of cell biology but also in the medicinal area, because of their potential applications against cancer, neurodegenerative disorders, viral infections, unicellular parasites, etc. One of the first molecules, roscovitine, is currently in phase 2 clinical trials against lung and nasopharyngeal cancers. It is also in phase 1 against glomerulonephritis. During the last few years his laboratory has been involved in the identification of drug targets by ways of affinity chromatography and yeast genetics methods. During a three year stay (ended August 2004) as a Visiting Professor in Paul GREENGARD’s (Nobel Prize laureate 2001) laboratory at the Rockefeller University, New York, he has been studying brain protein kinases and pharmacological inhibitors thereof.

LM is currently leading a small group (17 members) within the "Station Biologique de Roscoff", mostly focused on basic aspects of protein kinase regulation, as they relate to cancer, neurodegenerative disorders and malaria. He maintains a strong interest in kinase inhibitors (4 full time "screeners"). Besides cyclin-dependent kinases, he is developing the study of glycogen synthase kinase 3 (GSK3), casein kinase 1 (CK1), dual-specificity tyrosine phosphorylation-activated kinase (DYRK), three families of kinases with multiple implications in cellular functions, especially in Alzheimer’s disease and other neurodegenerative disorders. The laboratory is also studying the Plasmodium falciparum homologs of some of these kinases and screening for inhibitors. His team has developed expertise in cell biology, biochemistry, molecular biology, yeast genetics and pharmacology. LM is the author of over 200 scientific papers, inventor on 29 patents, editor of a series of books (6 volumes published), and founder of ManRos Therapeutics (“From Sea to Pharmacy”). He is recipient of several awards (such as the “Prix R. Rosen 2006 de Cancérologie de la Fondation pour la Recherche Médicale”, the 2003 Aventis Research Prize in Medicinal Chemistry, the CNRS Silver Medal (1997), the CNRS Bronze Medal (1984)). He was awarded a Honoris Causa Doctorate at the University Palacký, Olomouc, Czech Republic in 2004.

Selected Publications (5 max):

1. Meijer, L., Flajolet, M. and Greengard, P., 2004. Pharmacological inhibitors of glycogen synthase kinase-3. Trends Pharmacol. Sci. 25, 471-480.

2. Meijer, L., Skaltsounis, A.L., Magiatis, P., Polychronopoulos, P., Knockaert, M., Leost, M., Ryan, X.P., Vonica, C.D., Brivanlou, A., Dajani, R., Tarricone, A., Musacchio, A., Roe. S.M., Pearl, L. and Greengard, P., 2003. GSK-3 selective inhibitors derived from Tyrian purple indirubins. Chem. & Biol. 10, 1255-1266.

3. Meijer, L. and Raymond, E., 2003. Roscovitine and other purines as kinase inhibitors. From starfish oocytes to clinical trials. Accounts Chem. Res. 36, 417-425.

4. Hoessel, R., Leclerc, S., Endicott, J., Noble, M., Lawrie, A., Tunnah, P., Leost, M., Damiens, E., Marie, D., Marko, D., Niederberger, E.,Tang, W., Eisenbrand, G. and Meijer, L.,1999.Indirubin, the active constituent of a Chinese antileukaemia medicine, inhibits cyclin-dependent kinases. Nature Cell Biol. 1, 60-67.

5. Gray, N., Wodicka, L., Thunnissen, A. M., Norman, T., Kwon, S., Espinoza, F.H., Morgan, D.O., Barnes, G., Leclerc, S., Meijer, L., Kim, S.H., Lockhart, D.J. and Schultz, P.G., 1998. Exploiting chemical libraries, structure, and genomics in the search for new kinase inhibitors. Science 281, 533-538.