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Message: Domain-selective targeting of BET proteins in cancer and immunological diseases
https://www.sciencedirect.com/science/article/pii/S1367593120300193
Domain-selective targeting of BET proteins in cancer and immunological diseases
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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.
Introduction
Epigenetic mechanisms control the extent of acute and chronic inflammatory response, by driving the expression of transcription factors and cytokines which shape the phenotype of activated T cells, monocytes, and macrophages [1,2]. Epigenetic aberrations are at the heart of cancer development and progression by causing or influencing all cancer hallmarks [3]. Moreover, epigenetic processes play an essential role in the cross talk between immune and cancer cells in the tumor microenvironment [4].
The bromodomain and extraterminal domain (BET) family of epigenetic proteins consist of 4 paralogs: BRD4, BRD3, BRD2 (ubiquitously expressed), and BRDT (expressed only in testes) [5].
Genetic screens in tumor cells [6,7∗], in vitro and in vivo models of inflammation [8,9], as well as overexpression, chromosomal translocations, and genetic variants [10, 11, 12] have built a strong preclinical rationale for therapeutic targeting of BET proteins in cancer and inflammation [13].
Pharmacological inhibition of BET protein function started about a decade ago with the synthesis of (+)-JQ1 and I-BET [9,14] and has focused on targeting the tandem bromodomains (BDs), that are highly conserved among the 4 BET paralogs [15]. The BET BD1 and BD2 are druggable acetyl-lysine binding pockets [16,17] which mediate chromatin binding and interaction with transcription factors such as TWIST and Rel A [18,19]. Interestingly, pan-BET inhibitors (molecules such as iBET762 and (+)-JQ1 which target both BDs of all 4 BET paralogs) can induce a global reshaping of protein interactions around the BET proteins [20], suggesting that these inhibitors might perturb the function of the BET proteins beyond interfering with the binding to the substrates of the BD.
Pan-BET inhibitors have shown profound efficacy in preclinical models of cancer and inflammation [8,9,21, 22, 23, 24], and many are now progressing in clinical trials for the treatment of various cancers [25] (Table 1). Emerging data suggest that the administration of these agents results in target-driven safety signals such as thrombocytopenia, testis toxicity, and gastrointestinal toxicity, potentially preventing the assessment of the full potential of their mode of action [25]. It is likely that some of the toxic liabilities caused by pan-BET inhibitors are due to the interference with BET functions in contexts/tissues other than those targeted. For example, tests toxicity may be caused by interference with the functions of BRDT during spermatogenesis [26,27]. Similarly, thrombocytopenia may result from the inhibition of BRD3 during erythroid cell maturation, a process in which BRD3 has been shown to be involved [28].
Introduction
Epigenetic mechanisms control the extent of acute and chronic inflammatory response, by driving the expression of transcription factors and cytokines which shape the phenotype of activated T cells, monocytes, and macrophages [1,2]. Epigenetic aberrations are at the heart of cancer development and progression by causing or influencing all cancer hallmarks [3]. Moreover, epigenetic processes play an essential role in the cross talk between immune and cancer cells in the tumor microenvironment [4].
The bromodomain and extraterminal domain (BET) family of epigenetic proteins consist of 4 paralogs: BRD4, BRD3, BRD2 (ubiquitously expressed), and BRDT (expressed only in testes) [5].
Genetic screens in tumor cells [6,7∗], in vitro and in vivo models of inflammation [8,9], as well as overexpression, chromosomal translocations, and genetic variants [10, 11, 12] have built a strong preclinical rationale for therapeutic targeting of BET proteins in cancer and inflammation [13].
Pharmacological inhibition of BET protein function started about a decade ago with the synthesis of (+)-JQ1 and I-BET [9,14] and has focused on targeting the tandem bromodomains (BDs), that are highly conserved among the 4 BET paralogs [15]. The BET BD1 and BD2 are druggable acetyl-lysine binding pockets [16,17] which mediate chromatin binding and interaction with transcription factors such as TWIST and Rel A [18,19]. Interestingly, pan-BET inhibitors (molecules such as iBET762 and (+)-JQ1 which target both BDs of all 4 BET paralogs) can induce a global reshaping of protein interactions around the BET proteins [20], suggesting that these inhibitors might perturb the function of the BET proteins beyond interfering with the binding to the substrates of the BD.
Pan-BET inhibitors have shown profound efficacy in preclinical models of cancer and inflammation [8,9,21, 22, 23, 24], and many are now progressing in clinical trials for the treatment of various cancers [25] (Table 1). Emerging data suggest that the administration of these agents results in target-driven safety signals such as thrombocytopenia, testis toxicity, and gastrointestinal toxicity, potentially preventing the assessment of the full potential of their mode of action [25]. It is likely that some of the toxic liabilities caused by pan-BET inhibitors are due to the interference with BET functions in contexts/tissues other than those targeted. For example, tests toxicity may be caused by interference with the functions of BRDT during spermatogenesis [26,27]. Similarly, thrombocytopenia may result from the inhibition of BRD3 during erythroid cell maturation, a process in which BRD3 has been shown to be involved [28].
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