Structure and Photoactivatable Probes for Nucleic Acids and Kinases

Marie-Paule Teulade-Fichou

Marie-Paule Teulade-Fichou Team Leader Tel:

Our group works on the design of compounds targeting non-B nucleic acid structures and certain kinases involved in cancer. The group has a broad expertise in bio-organic chemistry and optical spectroscopy with a strong background in supramolecular chemistry and molecular recognition. Our final aims are to open new perspectives in the discovery of anticancer drugs and mechanistic tools.

 

Structure and Fluorescence Probes for G-quadruplex DNA and other non-B secondary structures.

Figure 1: Left) NMR structure of PhenDC3 ligand (in pink) bound to the c-myc quadruplex formed by the oncogene promoter sequence. Right) Overlap showing the perfect shape complementarity.
Figure 1: Left NMR structure of PhenDC3 ligand (in pink) bound to the c-myc quadruplex formed by the oncogene promoter sequence. Right) Overlap showing the perfect shape complementarity.

Over the past decade we developed a number of heterocyclic scaffolds and metal complexes able to bind specifically G-quadruplex DNA formed in strategic regions of the genome. The Phen-DC3 compound (Fig1) is one of the best quadruplex-probe used worldwide. We are also interested in targeting local pairing defects such as mismatched DNA using macrocycles (CBIs) of particular 3D topology. Our second line of research concerns the development of IR excitable 2 photon fluorescent probes for optical tracking of nucleic acids and proteins in cells.

 

Protein kinase Inhibitors

Figure 2: Purine derivative docked into the TYRO3 active site views from the Adenosine (A) and Allosteric (B) binding site
Figure 2: Purine derivative docked into the TYRO3 active site
views from the Adenosine (A) and Allosteric (B) binding site

Based on our long-term expertise in purine chemistry we have now in hands several chemical series likely to serve for protein kinase inhibitor discovery. The receptor tyrosine kinase Tyro3 is known to be involved in bladder cancer and to be over-expressed in other cancerous pathologies and therefore is considered a new therapeutic target. In collaboration with biologist and modeller partners at the Institut Curie and with crystallographers, we launched a multidisciplinary program for developing selective inhibitors of Tyro3 (Fig2).

 

Photosensitizers for Retinoblastoma

The current treatment for retinoblastoma, the most frequent eye tumour in children, exposes the patient to the long-term consequences of chemotherapy. We are exploring an alternative non-mutagenic treatment using glycoconjugated photosensitizers targeting overexpressed lectins specific of this tumour (Fig. 3)

Figure 3: Glycoconjugated Photosensitizers validated on Xenograft models of retinoblastoma .
Figure 3: Glycoconjugated Photosensitizers validated on Xenograft models of retinoblastoma .

 

The Institut Curie-CNRS Chemical library

This library is composed of 9000 compounds. Screenings of this collection have led to the identification of a number of inhibitors (LIM-kinase and phosphatase, HIV splicing proteins), now validated in preclinical trials. This has contributed to the creation of three start-up companies. (Abivax, Ecrin Therapeutics, Cellipse).

Key publications

Year of publication 2018

Prado Martins R., Findakly S., Daskalogianni C., Teulade-Fichou M.P., Blondel M., Fåhraeus R. (2018 Nov 29)

In Cellulo Protein-mRNA Interaction Assay to Determine the Action of G-Quadruplex-Binding Molecules

Molecules : 23 : 3124 : DOI : 10.3390/molecules23123124
Verga D., Nguyen C.H., Dakir M., Coll J.L., Teulade-Fichou M.P., Molla A. (2018 Nov 20)

Polyheteroaryl Oxazole/Pyridine-based compounds selected in vitro as G-quadruplex ligands inhibit Rock kinase and exhibit antiproliferative activity

Journal of Medicinal Chemistry : Just Accepted Manuscript : DOI : 10.1021/acs.jmedchem.8b01023
Hee-Sheung Lee, Mar Carmena, Mikhail Liskovykh, Emma Peat, Jung-Hyun Kim, Mitsuo Oshimura, Hiroshi Masumoto, Marie-Paule Teulade-Fichou, Yves Pommier, William C Earnshaw, Vladimir Larionov, Natalay Kouprina (2018 Nov 1)

Systematic Analysis of Compounds Specifically Targeting Telomeres and Telomerase for Clinical Implications in Cancer Therapy.

Cancer research : 78 : 6282-6296 : DOI : 10.1158/0008-5472.CAN-18-0894
M Lupu, Ph Maillard, J Mispelter, F Poyer, C D Thomas (2018 Nov 1)

A glycoporphyrin story: from chemistry to PDT treatment of cancer mouse models.

Photochemical & photobiological sciences : Official journal of the European Photochemistry Association and the European Society for Photobiology : 17 : 1599-1611 : DOI : 10.1039/c8pp00123e
Annalisa Patriarca, Charles Fouillade, Michel Auger, Frédéric Martin, Frédéric Pouzoulet, Catherine Nauraye, Sophie Heinrich, Vincent Favaudon, Samuel Meyroneinc, Rémi Dendale, Alejandro Mazal, Philip Poortmans, Pierre Verrelle, Ludovic De Marzi (2018 Nov 1)

Experimental set-up for FLASH proton irradiation of small animals using a clinical system

International Journal of Radiation Oncology • Biology • Physics : 102 : 619-626 : DOI : 10.1016/j.ijrobp.2018.06.403
Tom Baladi, Jessy Aziz, Florent Dufour, Valentina Abet, Véronique Stoven, François Radvanyi, Florent Poyer, Ting-Di Wu, Jean-Luc Guerquin-Kern, Isabelle Bernard-Pierrot, Sergio Marco Garrido, Sandrine Piguel (2018 Nov 1)

Design, synthesis, biological evaluation and cellular imaging of imidazo[4,5-b]pyridine derivatives as potent and selective TAM inhibitors.

Bioorganic & medicinal chemistry : 26 : 5510-5530 : DOI : 10.1016/j.bmc.2018.09.031
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