Domain-selective targeting of BET proteins in cancer and immunological diseases

• Published in: Current opinion in chemical biology Vol. 57; pp. 184 - 193
• Main Authors: Petretich, Massimo, Demont, Emmanuel H., Grandi, Paola
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.08.2020
• Subjects: Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; BD1; BD2; BET; Bromodomain; Cancer; Chemical probes; Drug Discovery; Humans; Immune System Diseases - drug therapy; Immune System Diseases - metabolism; Immunologic Factors - chemistry; Immunologic Factors - pharmacology; Inflammation; Inflammation - drug therapy; Inflammation - metabolism; Molecular Targeted Therapy; Neoplasms - drug therapy; Neoplasms - metabolism; ProTAC; Protein Domains - drug effects; Proteins - antagonists & inhibitors; Proteins - metabolism; Selectivity; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; BET; BD2; ProTAC; Selectivity; Inflammation; Bromodomain; Chemical probes; BD1; Cancer
• ISSN: 1367-5931; 1879-0402
• DOI: 10.1016/j.cbpa.2020.02.003

Cancer and inflammation are strongly interconnected processes. Chronic inflammatory pathologies can be at the heart of tumor development; similarly, tumor-elicited inflammation is a consequence of many cancers. The mechanistic interdependence between cancer and inflammatory pathologies points toward common protein effectors which represent potential shared targets for pharmacological intervention. Epigenetic mechanisms often drive resistance to cancer therapy and immunomodulatory strategies. The bromodomain and extraterminal domain (BET) proteins are epigenetic adapters which play a major role in controlling cell proliferation and the production of inflammatory mediators. A plethora of small molecules aimed at inhibiting BET protein function to treat cancer and inflammatory diseases have populated academic and industry efforts in the last 10 years. In this review, we will discuss recent pharmacological approaches aimed at targeting a single or a subset of the eight bromodomains within the BET family which have the potential to tease apart clinical efficacy and safety signals of BET inhibitors.