Bromodomain (BDs) modules of BET proteins regulate the expression of target genes. The deregulation of the cellular quantity of these proteins is related to the development of many diseases and especially cancers. BET family comprises 4 proteins (BRD4, BDR3, BRD2, BRDT) each having 2 bromodomains in tandem (BD1 and BD2). The use of "pan-BET" molecules, inhibiting the entire family without any selectivity, remains problematic in the clinic because they impact many regulatory pathways. The current major challenge is therefore to develop a selective molecule, with the aim of specifically targeting certain signaling pathways as a function of the pathology to be treated. Such inhibitors would be a tool of choice for the validation of each protein as a therapeutic target and would provide strong arguments for initiating a (pre)clinical study.
In the ongoing project, we aim to address the design, synthesis and biological evaluation of selective compounds with the objective to decipher the "individual" role of the two BDs present in the same protein and to specify the therapeutic interest of this selectivity. In addition to the chemistry and structural biochemistry performed routinely in the laboratory (synthesis and biophysical evaluation using ITC, HTRF, crystallography, etc.), we are currently able to carry out chemoproteomics, (epi)genomic (ChIP-seq/Chem-Seq) and cell-based studies (nanoBRET), to fully qualified lead compounds for future ex vivo and in vivo studies.
Géraldine Guasch (CRCM) - Publication dans Nature Communications -