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Thesis

French

ID: <

10670/1.93njg9

>

Where these data come from
Development of protein-protein interaction inhibitors targeting bromodomain-containing proteins : implications in epigenetics and cancer development.

Abstract

Bromodomain-containing proteins (BCPs) are especially involved in the regulation of gene transcription and cell signalling. Their dysregulation lead to the development of pathologies, such as inflammatory, cardiovascular diseases, and more particularly cancers. BCPs involved in the recognition of acetylated lysine of the histone tails, through their BromoDomain(s) module(s) (BDs). Among the eight families of BCPs, my thesis project focuses on the “BET” family. This family comprises four proteins which are composed of a tandem of two BDs each belonging to the BD1 or the BD2 subfamily. The architecture of the central cavity of the BDs, qualified as "druggable", allows the emergence of these proteins as new promising epigenetic targets. To date, about twenty clinical trials targeting different types of cancer have been initiated for "pan-BET" molecules that target all the members of this family. However, "pan-BET" inhibition is clinically problematic because it impacts many transcriptional pathways and causes the appearance of resistant cells. My thesis project is part of the current challenge is to develop more selective inhibitors, for example towards the BET-BD1 subfamily or the BET-BD2 subfamily or ideally towards one single BD inside the BET family. The development of such "selective epigenetic probes" targeting BET family BDs should allow deciphering their role and mechanism of action in various biological processes. Identifying "drug candidates" should lead to new targeted therapies and overcome the resistances related to the use of pan-BET molecules.

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