Kinase Biosensors and Inhibitors

Cyclin-dependent Kinases & Cancer 

One of the major hallmarks of cancer concerns deregulation of the mechanisms underlying cell proliferation, associated with genetic amplification, overexpression or hyperactivation of cell cycle regulators. In particular Cyclin-dependent kinases (CDK/cyclins) participate in a wide variety of essential biological processes including transcription, neuronal differentiation and metabolism, aside from the role they were first identified for in cell cycle progression. These kinases are hyperactivated in most human cancers, thereby contributing to sustain uncontrolled proliferation, and constitute attractive pharmacological targets for anticancer therapeutics. However there are currently no means of reporting on the activity of these targets directly in tumours. Moreover the only inhibitors of these kinases which are currently in clinical trials target the ATP-binding pocket.

Specifically our research focuses on detection and targeting of CDK4/CyclinD in lung cancer, melanoma and lymphoma, and on CDK5/p25 in neuronal cancers.

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FLUORESCENT BIOSENSORS for probing and imaging  cyclin-dependent kinases

In order to propose sensitive and adapted strategies for probing CDK/Cyclins, we have developed an original technology based on a toolbox of peptide and protein-based fluorescent biosensors which offers a straightforward means of sensing alterations in kinase levels, activity or conformation in vitro, in living cells and in vivo, when introduced into cells in an appropriate fashion, thanks to synthetic probes whose spectral properties are sensitive to environmental changes. 

These biosensors constitute sensitive tools for reporting on alterations associated with hyperactivation or inhibitrion of CDK/Cyclin kinases in real time in vitro, in living cells and in vivo. They offer a powerful technology for diagnostic purposes, to monitor response to therapeutics and to develop pharmacological screening strategies.

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TARGETING Cyclin-dependent kinases 

In order to propose novel inhibitors of cyclin-dependent kinases for anticancer therapeutics we are developing two approaches :
1-    Rational design of peptide and peptidomimetic inhibitors targeting protein/protein interfaces which are essential for CDK/Cyclin kinase function
2-    High throughput screening of chemical compound libraries for small molecules that target protein/protein interfaces or for allosteric inhibitors that perturb kinase function through conformational interference, thanks to specific fluorescent biosensors

 

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May C. Morris CNRS

 

Research Director

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Morgan Pellerano

 

CNRS Engineer

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Sébastien Diot

CNRS Enginner

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Sabrina Bedja

CNRS Engineer

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Arthur Laure

PhD Student

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FORMER MEMBERS

Carmen Tilmaciu (Post doc)

Juan-Antonio Gonzalez-Vera (Post doc)

Céline Bouclier (Post doc)

Camille Prével (PhD student)

Marion Peyressatre (PhD student)

Paula Gillman (ERASMUS internship)

Jessica Baliaka (M2 internship)

Ngoc Bao Nguyen (M2 internship)

Elvira Guegel (ERASMUS internship)

Jacques Saarbach (M2 internship)

PUBLICATIONS

Marion PeyressatreArthur LaureMorgan PelleranoHassan BoukhaddaouiInes SoussiMay C Morris (2020) Fluorescent Biosensor of CDK5 Kinase Activity in Glioblastoma Cell Extracts and Living Cells. Biotechnol J 2020 May 7;e1900474. doi: 10.1002/biot.201900474

Celine Bouclier, Matthieu Simon, Guillaume Laconde, Morgan Pellerano, Sebastien Diot, Sylvie Lantuejoul, Benoit Busser, Laetitia Vanwonterghem, Julien Vollaire, Véronique Josserand, Baptiste Legrand, Jean-Luc Coll, Muriel Amblard, Amandine Hurbin & May C. Morris (2020) Stapled peptide targeting the CDK4/Cyclin D interface combined with Abemaciclib inhibits KRAS mutant lung cancer growth. Theranostics, doi:10.7150/thno.40971.

Olivia Howells, Natasha Rajendran, Sarah Mcintyre, Pauline Henri, Yufei Liu, Owen Guy, Anthony E.G. Cass, May C. Morris, Sanjiv Sharma (2019) Microneedle array-based platforms for future theranostic applications ChemBioChem 20 (17):2198-2202 doi: 10.1002/cbic.201900112.

Henri P., & C. Prevel, M. Pellerano, J. Lacote, P.E. Stoebner, M. C. Morris* and L. Meunier* (2019) Psoriatic epidermis is associated with upregulation of CDK2 and inhibition of CDK4 activity , Br. J. Dermatol. doi: 10.1111/bjd.18178.

Pellerano M, Naud-Martin D, Mahuteau-Betzer F, Morille M, Morris MC (2019) Fluorescent biosensor for detection of the R248Q aggregation-prone mutant of p53. ChemBioChem, (4):605-613. doi: 10.1002/cbic.201800531.

Shvadchak, Volodymyr; Zgheib, Sarwat; Basta, Beata; Humbert, Nicolas; Langedijk, Johannes; Morris, M.C.; Ciaco, Stefano; Maskri, Ouerdia; Darlix, Jean-Luc; Mauffret, Olivier; Fossé, Philippe; Real, Eleonore; Mély, Yves (2018) Rationally designed peptides as efficient inhibitors of nucleic acid chaperone activity of HIV-1 nucleocapsid protein. Biochemistry 57(30):4562-4573. doi: 10.1021/acs.biochem.8b00527.

Martin C, Moors S, Danielsen M, Betti C, Fabris C, Sejer Pedersen D, Pardon E, Peyressatre M, Fehér K, Martins JC, Mosolff Mathiesen J, Morris M.C., Devoogdt N, Caveliers V, De Proft F, Steyaert J, Ballet S. (2017) Rational Design of Nanobody80 loop peptidomimetics : towards biased b2 adrenergic receptor ligands, Chemistry, Doi: 10.1002/chem.201701321.

Gonzalez-Vera JA, Bouclier C., Vazquez E. & Morris MC. (2017) Lanthanide-based peptide biosensor to monitor CDK4/Cyclin D kinase activity, Chemical Communications, 53, 6109 – 6112.

Pellerano M. , Tcherniuk S., Perals C., Van TNN., Garcin E., Mahuteau-Betzer F., Teulade-Fichou MP & Morris M.C. (2017) Targeting conformational activation of Cdk2 Biotechnology J. 12 (8) 1600531 doi: 10.1002/biot.201600531.

González-Vera JA, Fueyo-González F, Alkorta I, Peyressatre M, Morris MC, Herranz R (2016) Highly solvatochromic and tunable fluorophores based on a 4,5-quinolimide scaffold: novel CDK5 probes. Chem Commun 52, 9652-9655

Prével C., Pellerano M., Gonzalez Vera JA, Henri P., Meunier L., Vollaire J., Josserand V. & Morris M.C.  (2016) Fluorescent peptide biosensor for monitoring CDK4/cyclin D hyperactivity in melanoma cells, mouse xenografts and skin biopsies, Biosensors and Bioelectronics, 85:371-380. doi: 10.1016/j.bios.2016.04.050.

Pellerano M., Naud-Martin D., Peyressatre M., Prével C., Teulade-Fichou M.P, Mahuteau-Betzer M.P.* & Morris M.C. * (2016) TP2-Rho is a Sensitive Solvatochromic Red-shifted Probe for Monitoring the Interactions between CDK4 and Cyclin D ChemBioChem, special Issue Protein/Protein Interactions, 17(8), 737-44, DOI: 10.1002/cbic.201500641

Gonzalez-Vera JA & Morris M.C. (2015) Fluorescent Biosensors for probing the Dynamic Behaviour of Protein Kinases , Proteomes, 3, 369-410; doi:10.3390/proteomes3040369.

Tîlmaciu CM & Morris M.C. (2015) Carbon Nanotube Biosensors , Frontiers Chemical Biology, Front. Chem., 3 (59), 1-21 http://dx.doi.org/10.3389/fchem.2015.00059.

Floquet N, Costa MG, Batista PR, Renault P, Bisch PM, Raussin F, Martinez J, Morris MC, Perahia D. (2015) Conformational Equilibrium of CDK/Cyclin Complexes by Molecular Dynamics with Excited Normal Modes. Biophys J. 109(6):1179-89. doi: 10.1016/j.bpj.2015.07.003.

Peyressatre M., Prével C., Pellerano M., Morris M.C. (2015) Targeting Cyclin-Dependent Kinases in Human Cancers : from small molecules to peptide inhibitors. Cancers  7(1):179-237.

Hamdi A., Lesnard A., Suzanne P., Robert T., Miteva M.A., Pellerano M., Didier B., Ficko-Blean E., Lobstein A., Hibert M., Rault S., Morris M.C. & Colas P. (2015) Tampering with cell division by using small molecule inhibitors of CDK-CKS protein interactions. ChemBioChem 16(3):432-9.

Prével C., Kurzawa L., Van T.N.N. & Morris MC (2014) Fluorescent biosensors for drug discovery- New tools for Old Targets – Screening for Inhibitors of Cyclin-dependent kinases. European Journal of Medicinal Chemistry. 88, 74-88.

Van TNN., Pellerano M., LyKaSo S. & Morris MC (2014) Fluorescent biosensor for probing CDK/Cyclin kinase activity in vitro and in living cells, ChemBioChem. 15 (15) 2298-2305.

Prével, C., Pellerano, M., Van, T.N.N., Morris, M.C. (2014) Fluorescent Biosensors for High Throughput Screening of Protein Kinase Inhibitors. Biotechnology J. 9(2) 253-265.

Morris MC.(2014) Spotlight on Fluorescent Biosensors—Tools for Diagnostics and Drug Discovery. ACS Chem.Med.Lett.,  5, 99-101 DOI: 10.1021/ml400472e.

Ligue Regionale Contre le Cancer (2020-2021) “Application de biosenseurs fluorescents au profilage d’activités kinases dans les cancers humains”.

MATWIN prize (2019-2020): CDK4PPI: “Inhibiteurs allostériques de CDK4”.

Project READYNOV/FEDER (2019-2020) «KINPEP: Développement de biosenseurs peptidiques pour la détection et la quantification d'activités kinases associées au cancer et aux pathologies neuronales» déposé dans le cadre de l’AAP READYNOV 2018. Partenariat avec la société GENEPEP.

Labeling KIM « Biomarkers & Therapy » of MUSE in 2018.

Ligue Regionale Contre le Cancer (2016) “Etude de l’activité des CDK/cyclines à l’aide de biosenseurs fluorescents : application aux effets des rayons ultraviolets sur la peau et aux cancers cutanés”.

GSO Emergence Technologies pour la Santé (Juillet 2015-2016) “Detection et suivi du glioblastoma par quantification de l’activité de CDK5”.


INCA - Programme translationnel PRT-K 2014 (Juin 2015-2018)   « FOLDLUNGK4 – Ciblage de la kinase CDK4/Cycline D par des foldamères et application thérapeutique au cancer du poumon ».


ANR (Dec 2013-Dec 2017)   « NANOMULTISENS : Nanosenseurs multifonctionnels pour la detection de protéines kinases intracellulaires constituant des biomarqueurs cancéreux».
 

GRANT & FUNDING SOURCES

©IBMMPharmaco2020