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 2017

Pabon-Martinez Y.V., Xu Y., Villa A., Lundin K.E., Geny S., Nguyen C.H., Pedersen E.B., Jorgensen P.T., Wengel J., Nilsson L., Smith C.I.E., Zain R. (2017 Sep 8)

LNA effects on DNA binding and conformation: from single strand to duplex and triplex structures

SCIENTIFIC REPORTS : 7 : DOI : 10.1038/s41598-017-09147-8
Pauline Gilson, Fernando Josa-Prado, Claire Beauvineau, Delphine Naud-Martin, Laetitia Vanwonterghem, Florence Mahuteau-Betzer, Alexis Moreno, Pierre Falson, Laurence Lafanechère, Véronique Frachet, Jean-Luc Coll, Jose Fernando Díaz, Amandine Hurbin, Benoit Busser (2017 Sep 2)

Identification of pyrrolopyrimidine derivative PP-13 as a novel microtubule-destabilizing agent with promising anticancer properties.

Scientific reports : 10209 : DOI : 10.1038/s41598-017-09491-9
Foy J.P., Bazire L., Ortiz-Cuaran S., Deneuve S., Kielbassa J., Thomas E., Viari A., Puisieux A., Goudot P., Bertolus C., Foray N., Kirova Y., Verrelle P., Saintigny P. (2017 Sep 1)

A 13-gene expression-based radioresistance score highlights the heterogeneity in the response to radiation therapy across HPV-negative HNSCC molecular subtypes

BMC MEDICINE : 15 : DOI : 10.1186/s12916-017-0929-y
Lista M.J., Martins R.P., Angrand G., Quillevere A., Daskalogianni C., Voisset C., Teulade-Fichou M.P., Fahraeus R., Blondel M. (2017 Sep 1)

A yeast model for the mechanism of the Epstein-Barr virus immune evasion identifies a new therapeutic target to interfere with the virus stealthiness

MICROBIAL CELL : 4 : 305-307 : DOI : 10.15698/mic2017.09.590
Buchieri Maria V., Cimino Mena , Rebollo-Ramirez Sonia, Beauvineau Claire, Cascioferro Alessandro, Favre-Rochex Sandrine, Helynck Olivier, Naud-Martin Delphine, Larrouy-Maumus Gerald, Munier-Lehmann Hélène, Gicquel Brigitte (2017 Aug 28)

Nitazoxanide Analogs Require Nitroreduction for Antimicrobial Activity in Mycobacterium smegmatis

Journal of Medicinal Chemistry : DOI : 10.1021/acs.jmedchem.7b00726
Aziza Jessy, Piguel Sandrine (2017 Aug 25)

An update on direct C–H bond functionalization of nitrogen-containing fused heterocycles

Synthesis : 49 : DOI : 10.1055/s-0036-1590859
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