The Marseille Cancer Research Center celebrates its 50th anniversary ! -
Drug discovery is an inherently inefficient process, particularly in oncology. The difficulty in matching the immense and complex chemical world with a desired physiological effect is illustrated by limitations such as harmful side effects and drug resistance, which defy the most powerful chemotherapeutics available. Novel therapeutic targets and new ways to identify, to characterize and to develop anti-cancer drugs are needed.
Most drug discovery efforts by pharmaceutical companies concern the development and/or expansion of their pre-clinical and clinical pipeline primarily targeting G protein-coupled receptors, nuclear receptors, ion channels and the active sites of enzymes (eg kinases). Although this strategy is understandable for historical reasons and risk management, inhibitors of protein-protein interaction represents an alternative and almost unexplored reservoir for drug development in oncology. Thus, targeting protein-protein interaction interfaces appears a valuable and promising strategy, which is further underscored by an expected reduced occurrence of resistance that might arise due to mutations in the protein-protein interface.
In this context, our objectives are to identify, to understand, to validate and to target protein-protein interaction interfaces critically involved in tumor cell signaling, with the specific purpose of facilitating the transfer of therapeutic and pharmacological targets into preclinical and clinical development programs in oncology.
Bromodomains (BDs) are protein domains that recognize chemical modification patterns on DNA to regulate the expression of target genes. The deregulation of these proteins and in particular the BET protein family is involved in the development of many diseases, including cancers. The BET family is composed of 4 proteins each containing two bromodomains called BD1 and BD2.
Many drugs that recognize the bromodomains of whole BET family have been recently described. They are called Pan-BET inhibitors but their use in clinical studies is problematic as many transcription pathways are impacted and can lead to the emergence of resistances.
The main goal of this research project consists in developing BD1 and BD2 selective inhibitors as chemical probes as well as new potential drug candidates.
Immune checkpoints are a unique class of Protein-Protein Interactions (PPIs) that control immune responses and are powerful targets for reversing tumor-induced immunosuppression and enabling tumor elimination.
Our group is using our PPI-targeting expertise to develop the next generation of immunotherapies using small molecules.
Modulating the tumor immune microenvironment using small molecules offers advantages that are complementary to and potentially synergistic with the use of antibody and cellular therapies as well as conventional therapies (radiation and chemotherapy), including the potential for oral bioavailability, improved solid tumor penetration, and the adaptability to combination therapies.
Our goal is to develop novel small molecule-based immunotherapies using a hybrid multidisciplinary approach blending lead-like and fragment-based high-throughput screening (chemotype discovery) with structure-based and in silico guided drug design (chemotype evolution). In addition, we are developing novel in vitro models to better evaluate the complex mechanism of action of immunomodulatory small molecules and predict their in vivo activity.
As a proof of concept for our approach, we are developing novel small molecule inhibitors of the innate immune checkpoint SIRPα-CD47—a longstanding target of interest for our group
Our aim is to produce SIRPα-CD47 inhibitors with better selectivity for the tumor immune microenvironment, lower toxicity, enhanced solid tumor penetration, and greater anti-tumor efficacy than current blocking antibodies.
Molecular Modelling Tools
The team
iSCB Team 2023
iSCB Team 2021
iSCB Team 2019
iSCB Team 2020
Team publications
Hammam K, Saez-Ayala M, Rebuffet E, Gros L, Lopez S, Hajem B, Humbert M, Baudelet E, Audebert S, Betzi S, Lugari A, Combes S, Letard S, Casteran N, Mansfield C, Moussy A, De Sepulveda P, Morelli X, Dubreuil P
Hoffer L, Garcia M, Leblanc R, Feracci M, Betzi S, Ben Yaala K, Daulat AM, Zimmermann P, Roche P, Barral K, Morelli X
Carrasco K, Montersino C, Derviaux C, Saez-Ayala M, Hoffer L, Restouin A, Castellano R, Casassa J, Roche P, Pasquier E, Combes S, Morelli X, Collette Y, Betzi S
Calbert ML, Chandramouly G, Adams CM, Saez-Ayala M, Kent T, Tyagi M, Ayyadevara VSSA, Wang Y, Krais JJ, Gordon J, Atkins J, Toma MM, Betzi S, Boghossian AS, Rees MG, Ronan MM, Roth JA, Goldman AR, Gorman N, Mitra R, Childers WE, Graña X, Skorski T, Johnson N, Hurtz C, Morelli X, Eischen CM, Pomerantz RT
Montserrat-Gomez M, Gogl G, Carrasco K, Betzi S, Durbesson F, Cousido-Siah A, Kostmann C, Essig DJ, Strømgaard K, Østergaard S, Morelli X, Trave G, Vincentelli R, Bailly E, Borg JP
Leblanc R, Ghossoub R, Goubard A, Castellano R, Fares J, Camoin L, Audebert S, Balzano M, Bou-Tayeh B, Fauriat C, Vey N, Garciaz S, Borg JP, Collette Y, Aurrand-Lions M, David G, Zimmermann P
