Bromodomains (BDs) are small protein domains capable of recognizing chemical modifications of DNA responsible for regulating gene expression. Deregulation of these proteins, and in particular of the BET family, is implicated in the development of numerous diseases, particularly cancers. This family comprises 4 proteins, each with two bromodomains called BD1 and BD2.

Numerous small molecules targeting the bromodomains of the entire BET family have recently been described. These are known as Pan-BET inhibitors, but their use in clinical studies remains problematic, as they impact numerous transcription pathways, which can lead to the emergence of resistance phenomena.

Structure based drug design

Immune checkpoints are a class of protein-protein interactions (PPIs) that control the immune response and represent major targets for countering tumor-induced immunosuppression and tumor elimination.

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
• 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.