Institut de Chimie de Nice UMR 7272

The central theme of our research is synthetic organic chemistry with a focus on the development of new synthetic methods based on various aspects of modern strategies including catalysis, tandem and multicomponent transformations, radical processes and their applications to the synthesis of biologically active molecules.

Developing new therapeutics for unmet medical needs and particularly in oncology continues to be an important focus of modern drug discovery. Our group is highly involved in the design, synthesis and validation of new ‘smart’ bioactive molecules featuring functional properties allowing them to interfere with several key biological processes including the metabolism, immune response and DNA damage checkpoint of cancer and cancer stem cells. Therefore, our drug discovery programs mainly focus on (i) the development of new smart small molecules to overcome drug resistance in oncology, through translational research with a closer integration, at an early stage, of chemistry/biology/clinic and industrial approaches ; and (ii) the identification & validation of new targets using chemical biology and “omics” approaches. To achieve this goal several collaborations have been established around the world with both academic and industrial partners.

o Targeting GRP78/Bip in cancer

Melanoma is an aggressive form of skin cancer that occurred in more than 230000 people and resulted in 55000 deaths in 2012, mainly in developed countries. Despite significant progress brought by the new anti-Braf and anti-PD1 targeted therapies, patients in the metastatic phase have a median life expectancy of only 8 - 9 months, because of the rapid emergence of resistance to these treatments. Thus it is of utmost importance to find new therapeutic approaches to treat these diseases.

GRP78 is a chaperone enzyme responsible for helping the proper folding of proteins synthesized in the ribosomes. It also acts as a molecular sensor of non-/misfolded protein accumulation, and triggers a cellular protection mechanism called UPR (Unfolded Protein Response) slowing down protein synthesis, and aiding the proper folding or the evacuation of these malformed proteins. Recently, we demonstrated, in collaboration with biologist partners from the Mediterranean Centre of Molecular Medicine (C3M) that the inhibition of GRP78 and UPR allowed circumventing these resistance phenomena by selectively inducing cell death in melanoma cells, without causing side effects or toxicity in non-cancerous cells. Therefore, we have developed new compounds inhibiting GRP78, active in vitro and in vivo, and displaying good pharmacological properties.

o Tackling the inflammation/angiogenesis axis in oncology

Inflammation and angiogenesis are two integrated processes. Our team develops series of small sized therapeutic agents able to interfere upstream and downstream of the corresponding signaling pathway.

• New CXCL/CXCR antagonists : ongoing studies. We focused this project on the CXCL cytokine family because its leading member (IL-8) : (i) is abundantly secreted where and when VEGF is produced, (ii) its expression is comparable to these of VEGF, and (iii) the molecular factors of VEGF expression stimulate also IL-8 expression. As proof-of-concept, we already demonstrated that SB225002, a known competitive CXCR antagonist, inhibits tumor growth, angiogenesis and inflammation in vitro and in vivo in Clear Cell Renal Cell Carcinoma model (786-O cell line) by antagonizing the effect of CXCL 1, 7 and 8. We are currently working on the conception and the synthesis of new series of CXCR antagonists.

• New Neuropilin antagonists. Neuropilin-1 (Nrp-1) is an VEGF-A co-receptor whose overexpression in tumor tissues is clinically related to a poor prognosis. We have developed the two first series of small-sized and non-peptidic Nrp-1 antagonists. The two lead compounds exert significant in vitro and in vivo anti-angiogenic and anti-tumor activities. We are currently working on : (i) deciphering the precise way-of-action of these lead compounds and (ii) optimizing their pharmacological profile.

o Dual activation of autophagy and apoptosis to kill resistant cancer cells

Drug resistance is a major obstacle that limits the effectiveness of cancer therapy. Many cancer cells acquire resistance mechanisms that allow them to hamper apoptosis induction, contributing to initiation and progression of cancers. Therefore, novel therapeutic strategies are of great interest to address the emerging problem of drug resistance. Recent studies have suggested that the induction of autophagy, another type of cellular death mechanism different from apoptosis, could be a useful therapeutic approach to overcome drug resistance of cancers to some therapeutic agent, particularly those that typically induce an apoptotic response. Moreover, the existence of a complex functional relationship between apoptosis and autophagy can lead to cross-activation. Thus, the design of new chemotherapeutics able to induce simultaneously or consequently these two cell death types constitute an appealing approach to circumvent drug resistance. In this context we recently reported on novel nucleosides analogs able to revert the resistance to standard treatments in various haematological maligencies. For instance, we proved the efficacy of our nucleoside analogs, in vivo, on mice xenografted with the highly aggressive SKM1R cell line (myelodysplastic syndrome) whereas the first line treatment, azacitidine, is inefficient.

Ongoing studies concerning this dual targeting of apoptosis and autophagy are focused on (i) the understanding of the precise mode of action of our nucleoside analogs and (ii) the expansion of their application to non-hematological malignancies.

o Development of small molecules in cancer immunotherapy

Immune-checkpoint blockades are recent, major breakthroughs in cancer therapy but the response rate remains low (10% to 57% depending on the cancer type and the treatment combinations). While this approach relies on the use of large macromolecular structures (anti-bodies : anti-PD1, anti-PDL1) that “boost” the immune system, we are currently investigating the use of small synthetic organics able to potentiate both/either the immune system itself and/or the action of the anti-PD(L1). Our ongoing research in this field is mainly focused on the discovery of small therapeutics able to act synergistically with anti-PD1 antibodies (nivolumab, pembrolizumab).Immune-checkpoint blockades are recent, major breakthroughs in cancer therapy but the response rate remains low (10% to 57% depending on the cancer type and the treatment combinations). While this approach relies on the use of large macromolecular structures (anti-bodies : anti-PD1, anti-PDL1) that “boost” the immune system, we are currently investigating the use of small synthetic organics able to potentiate both/either the immune system itself and/or the action of the anti-PD(L1). Our ongoing research in this field is mainly focused on the discovery of small therapeutics able to act synergistically with anti-PD1 antibodies (nivolumab, pembrolizumab).

This part of research is focused on the chemistry and biochemistry of natural and artificial nucleosides and nucleic acids, with special emphasis on functional and structural properties of artificial short DNA and RNA. We also focus on the development of new synthetic methodologies using post-synthetic modifications with the aim of investigating functional key features of these important biomolecules in catalysis, labelling, cross-linking ... Biophysical properties and Biological activity of artificial nucleobases (DNA and RNA targeting, oligonucleotides and small molecule ligands), nucleosides, nucleotides and oligonucleotides is systematically studied in collaboration with several groups.

Multicomponent reactions

Rational design of DNA and RNA Ligands (Super-bases & supramolecular recognition)

Applications in DNAs targeting (artificial oligonucleotides TFO)

Applications in RNAs targeting