JCJC SIMI 7 - JCJC - SIMI 7 - Chimie moléculaire, organique, de coordination, catalyse et chimie biologique

Targeting of oncogenic microRNAs : toward new chemotherapies – CImiR

Targeting oncogenic microRNAs: toward new chemotherapies

One of the most amazing discoveries of the past decade in genetic oncology is that cancer is related not only to alterations of protein coding genes but also to alterations of non-coding RNAs, known as microRNAs (miRNAs). The purpose of this project is the development of small-molecule drugs targeting specific oncogenic miRNAs’ production. This is a very promising approach that would open the way for innovative targeted cancer therapy.

Design and synthesis of new small-molecule ligands targeting oncogenic microRNAs

MicroRNAs (miRNAs) are a recently discovered category of small RNA molecules that regulate gene expression at the post-transcriptional level. Accumulating evidence indicates that miRNAs are aberrantly expressed in a variety of human diseases including cancer, immune disorders and cardiovascular pathologies. For these reasons, it is now clear that the inhibition of oncogenic miRNAs (defined as the blocking of miRNAs’ production or function) would find application in the therapy of different types of cancer in which these miRNAs are implicated.<br />The purpose of this project is the development of small-molecule drugs targeting specific oncogenic miRNAs production. This is a very promising approach that would open the way for innovative targeted cancer therapy. In particular, we chose to target two oncogenic miRNAs (miRNA-372 and miRNA-373) implicated in gastric cancer, which is the fourth most common cancer and the second leading cause of cancer death in the world. These two oncogenic miRNAs are overexpressed in gastric cancer cells starting from their precursors (pre-miRNA-372 and pre-miRNA-373): two stem-loop structured RNAs which lead to mature miRNAs after cleavage by the enzyme Dicer in the cytoplasm. A compound able to interfere with the cleavage of these pre-miRNAs by the enzyme Dicer will inhibit the production of oncogenic miRNAs and restore normal mRNA translation finally leading to cancer regression.

The purpose of this project is the development of small-molecule drugs targeting specific oncogenic miRNAs production. In particular, we chose to target two oncogenic miRNAs (miRNA-372 and miRNA-373) implicated in gastric cancer, which is the fourth most common cancer and the second leading cause of cancer death in the world. These two oncogenic miRNAs are overexpressed in gastric cancer cells starting from their precursors (pre-miRNA-372 and pre-miRNA-373): two stem-loop structured RNAs which lead to mature miRNAs after cleavage by the enzyme Dicer in the cytoplasm. A compound able to interfere with the cleavage of these pre-miRNAs by the enzyme Dicer will inhibit the production of oncogenic miRNAs and restore normal mRNA translation finally leading to cancer regression. Toward this aim, we plan to (i) synthesize new potential RNA ligands designed to target specifically and with high affinity the stem-loop structure of pre-miRNAs-372 and 373, (ii) evaluate their ability to bind pre-miRNAs and inhibit Dicer cleavage using a cell-free assay that we will develop in our laboratory and (iii) take advantage of this assay in order to screen a library of different chemical compounds.
After the identification of active compounds following these two strategies, we intend to study more in detail their exact site of interaction as well as their selectivity toward other nucleic acid structures (RNAs and DNA). The most active compounds will be finally evaluated in cells for the specific inhibition of pre-miRNA372/3 processing (for the inhibition of mature oncogenic miRNA production) as well as for their cytotoxicity against gastric cancer cells.
Our final aim is to identify one or more lead molecules that could be further modified in order to optimize their biological activity and their pharmacological profile until the discovery of new efficient anticancer agents acting as oncogenic miRNAs inhibitors.

So far, we performed the synthesis and the biological evaluation of a new series of small-molecule RNA ligands These consists of the conjugation of two RNA binding motives, i.e. the aminoglycoside neomycin and different natural and artificial nucleobases, in order to obtain ligands with increased affinity and selectivity compared to parent compounds. After the synthesis of this new series of RNA ligands, we demonstrated that they are able to inhibit the production of the oncogenic miRNAs by binding targeted pre-miRNAs and inhibiting their processing by Dicer. Moreover, we proved that some of these compounds bear an anti-proliferative activity toward gastric cancer cells and that this activity is directly linked to a decrease in the production of targeted miRNAs. Despite the low number of examples of small molecules targeting oncogenic miRNAs, such inhibitors could be extremely useful for the development of new anticancer therapeutic strategies. This is the first time that a rational approach is proposed in order to target miRNAs with small molecules.

Our aim is to identify lead molecules that could be further modified in order to optimize their biological activity and their pharmacological profile until the discovery of new efficient anticancer agents acting as oncogenic miRNAs inhibitors. The novelty of this project resides first of all in the choice of the target, since miRNA production and function is still largely unknown. Although the possibility to specifically target miRNAs with small molecules has already been proven by chemical library screening, the approach that we propose is original as it is the first time that the rational design of RNA ligands targeting miRNAs is presented. Our experience in the design of specific RNA ligands as well as in the biophysical study of the involved interactions will be the main force to successfully lead the project. Finally, even if the newly synthesized compounds were not specific for the targeted miRNAs, but general miRNA inhibitors, they can then be employed as useful biochemical tools in order to study the biological function of other miRNAs.

- Oral communication à EFMC-ISMC 2012 : International Symposium on Medicinal Chemistry, 2-6 septembre 2012, Berlin, Germany
- Submitted publication : Targeting the production of oncogenic microRNAs with multifunctional synthetic small molecules

MicroRNAs (miRNAs) are a recently discovered category of small RNA molecules that regulate gene expression at the post-transcriptional level. Accumulating evidence indicates that miRNAs are aberrantly expressed in a variety of human diseases including cancer, immune disorders and cardiovascular pathologies. For these reasons, it is now clear that the inhibition of oncogenic miRNAs (defined as the blocking of miRNAs production or function) would find application in the therapy of different types of cancer in which these miRNAs are implicated.
The purpose of this project is the development of small-molecule drugs targeting specific oncogenic miRNAs production. This is a very promising approach that would open the way for innovative targeted cancer therapy. In particular, we chose to target two oncogenic miRNAs (miRNA-372 and miRNA-373) implicated in gastric cancer, which is the fourth most common cancer and the second leading cause of cancer death in the world. These two oncogenic miRNAs are overexpressed in gastric cancer cells starting from their precursors (pre-miRNA-372 and pre-miRNA-373): two stem-loop structured RNAs which lead to mature miRNAs after cleavage by the enzyme Dicer in the cytoplasm. A compound able to interfere with the cleavage of these pre-miRNAs by the enzyme Dicer will inhibit the production of oncogenic miRNAs and restore normal mRNA translation finally leading to cancer regression.
In order to discover new and efficient inhibitors of oncogenic miRNA production, we propose (i) the design and the synthesis of new RNA ligands conceived in order to bind at the stem-bulge and/or stem-loop junction sites on the pre-miRNA sequence and (ii) the concomitant development of an appropriate high throughput cell-free assay to test in vitro the newly synthesized compounds for their ability to inhibit miRNA production. In order to take advantage of the development of this test, we will also (ii) apply this assay to the screening of a chemical library to discover new and unexpected pre-miRNAs binders. After the identification of active compounds by this in vitro assay, we intend to study more in detail their exact site of interaction as well as their selectivity toward other nucleic acid structures (RNAs and DNA). The most active compounds will be finally evaluated in cells for the specific inhibition of pre-miRNA372 and premiRNA-373 as well as for their cytotoxicity against gastric cancer cells.
Our aim is to identify lead molecules that could be further modified in order to optimize their biological activity and their pharmacological profile until the discovery of new efficient anticancer agents acting as oncogenic miRNAs inhibitors. The novelty of this project resides first of all in the choice of the target, since miRNA production and function is still largely unknown. Although the possibility to specifically target miRNAs with small molecules has already been proven by chemical library screening, the approach that we propose is original as it is the first time that the rational design of RNA ligands targeting miRNAs is presented. Our experience in the design of specific RNA ligands as well as in the biophysical study of the involved interactions will be the main force to successfully lead the project. Finally, even if the newly synthesized compounds were not specific for the targeted miRNAs, but general miRNA inhibitors, they can then be employed as useful biochemical tools in order to study the biological function of other miRNAs.

Project coordination

Maria DUCA (CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE - DELEGATION REGIONALE COTE D'AZUR) – maria.duca@unice.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

LCMBA CNRS UMR6001 CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE - DELEGATION REGIONALE COTE D'AZUR

Help of the ANR 154,982 euros
Beginning and duration of the scientific project: December 2011 - 30 Months

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