JCJC SIMI 7 - JCJC : Sciences de l'information, de la matière et de l'ingénierie : Chimie moléculaire, organique, de coordination, catalyse et chimie biologique

Rational synthesis of compounds derived from a natural product, targeting two antiapoptotic proteins – APO-MeioA

Rational synthesis of compounds derived from a natural product, targeting two antiapoptotic proteins

The project, developped at the Institut de Chimie des Substances Naturelles (UPR2301, CNRS) aims at elaborating original anticancer compounds targeting two proteins of the Bcl-2 family that is implicated in the programmed cell death (PCD). These compounds are derived from a natural compound, meiogynin A, previously isolated and synthesized in our group. The strength of the project relies on the collaboration with an NMR and a molecular modelling team.

Development of a drug candidate derived from a natural product targeting a family of proteins that are deregulated in some cancers

Cancer still remains one of the main causes of death in France, hence fight against this terrible disease is a major public health objective. One of the approaches to provide an answer to this crucial issue is to develop drugs that act through a different action mechanism from those already in clinical use. An emerging therapeutic strategy consists in targeting proteins involved in apoptosis (programmed cell death) that are deregulated in some cancers. Our research project, developed at CNRS-ICSN-UPR 2301, aims at developing compounds, with anticancer properties, targeting two proteins involved in apoptosis: Bcl-xL and Mcl-1. For this, we have elaborated, by chemical synthesis, derivatives of meiogynin A, a natural product isolated in our team from a plant, that has a significant activity on these target proteins. Natural products are, indeed, an invaluable source of new molecules that can be used thereof in therapy or as precursors for the formation of active products. Thus, according to the review of Newman and Cragg, 42% of new anticancer drugs marketed between 1981 and 2006 came from natural products or their derivatives.

In order to meet objectives of this research program, the teams involved in the project have implemented different methods and techniques:
- Techniques in organic chemistry to set up a selective synthesis of the desired compounds,
- Techniques in biology to produce the target proteins Bcl-xL and Mcl-1 and to implement an efficient and robotized biological assay in order to evaluate the activities of the synthetic compounds on these proteins,
- Nuclear magnetic resonance (NMR) techniques so as to determine the precise binding site of meiogynin A and of the synthetic compounds within the target proteins Bcl-xL and Mcl-1,
- Techniques of molecular modelling to make drug design, docking meiogynin A and the synthetic compounds in Bcl-xL and Mcl-1 to provide chemical modifications to make them more active.

Biological tests on the two target proteins Bcl-xL and Mcl-1 were developed and robotized. The detailed study of the interactions of Bcl-xL and Mcl-1 with meiogynin A and synthetic compounds was performed by NMR and yielded information that has guided molecular modeling studies. The latter proposed a binding mode of meiogynin A as well as chemical modifications to perform. The first chemical changes have led to analogues of the first generation, as active as meiogynin A on target proteins, but also cytotoxic.
A second-generation of analogues has then been elaborated (synthetic strategy developed on a multi gram scale). One of the compounds is fifty times more potent than meiogynin A on both proteins. It is one of the most potent pan-inhibitors reported in the literature.
Two new partnerships were developed, one with a team of biologists at the Institut Gustave Roussy (Villejuif) and another one with a team specialized in mass spectrometry at ICSN. In the course of this project, a new chemical reaction was highlighted and developed. In addition, new natural products have been isolated using a bioguided strategy thanks to the biological tests that were set up.

The molecules elaborated throughout this projetc are among the most potent pan-inhibitors reported in the literature. Research is underway in our laboratory to develop more cytotoxic derivatives.
The ApomeioA project has strengthened intra ICSN collaborations that will last beyond the project. It allowed the establishment of a new collaboration with a team of biologist at IGR. Biological tests developed with this funding will be operated at a larger scale.

Publications :
1.Dardenne, J., Guéritte, F., Roussi, F. Eur. J. Org.Chem., 2013, 2116-2122.
2.S. Desrat, A. Pujals, C. Colas, J. Dardenne, C. Geny, L. Favre, V. Dumontet, B. Iorga, M. Litaudon, M. Raphaël, J. Wiels, F. Roussi Bioorganic & M

Apoptosis is the programmed cell death (PCD) used by multicellular organisms to regulate tissue homeostasis through the elimination of useless or potentially harmful cells. Disruption of this process is implicated in many kinds of diseases such as cancer. The Bcl-2 family of proteins governs the commitment to PCD at the mitochondrion (the intrinsic apoptotic pathway). It is divided into antiapoptotic such as Bcl-xL or Mcl-1 and proapoptotic proteins such as Bax, Bad or Bim.
This proposal aims to elaborate original compounds with anti-cancer properties, targeting Bcl-xL and Mcl-1.
Recently, Meiogynin A, a new dimeric sesquiterpenoid has been isolated. It acts as an antagonist to the Bcl-xL/Bak association. The principal investigator has already performed a short, convergent and selective total synthesis of meiogynin A.
A scientific programme will be developed in order to elaborate more potent analogues of meiogynin A, targeting not only Bcl-xL but also Mcl-1. Preliminary molecular modelling studies will be performed (in silico screening) in order to design compounds that could interfere with both targeted proteins. These compounds will be synthesized. Their binding affinities will be evaluated using a fluorescence polarization assay that will be settled in the laboratory for that purpose. The binding site of active compounds on Bcl-xL and Mcl-1 will be determined by NMR experiments. According to these preliminary results, a second molecular modelling study will be performed in order to design refined structures. These compounds will be synthesised, their biological activity will be evaluated and their binding sites will be determined.

--> elaboration of a drug candidate by an iterative process

Project coordinator

Madame Fanny ROUSSI (CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE - DELEGATION REGIONALE ILE-DE-FRANCE SECTEUR SUD) – fanny.roussi@icsn.cnrs-gif.fr

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

CNRS-ICSN CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE - DELEGATION REGIONALE ILE-DE-FRANCE SECTEUR SUD

Help of the ANR 240,000 euros
Beginning and duration of the scientific project: - 48 Months

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