Epigenetic modifications, specifically acetylation of histone plays a decisive role in gene regulation and transcription of normal cellular mechanisms and pathological conditions. The bromodomain and extraterminal (BET) proteins (BRD2, BRD3, BRD4, and BRDT), being epigenetic readers, ligate to acetylated regions of histone and synchronize gene transcription. BET proteins are crucial for normal cellular processing as they control cell cycle progression, neurogenesis, differentiation, and maturation of erythroids and spermatogenesis, etc. Research-based evidence indicated that BET proteins (mainly BRD4) are associated with numeral pathological ailments, including cancer, inflammation, infections, renal diseases, and cardiac diseases. To counter the BET protein-related pathological conditions, there are some BET inhibitors developed and also under development. BET proteins are a topic of most research nowadays. This review, provides an ephemeral but comprehensive knowledge about BET proteins’ basic structure, biochemistry, physiological roles, and pathological conditions in which the role of BETs have been proven. This review also highlights the current and future approaches to pledge BET protein-related pathologies.

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A Comprehensive Review of BET Protein Biochemistry, Physiology, and Pathological Roles

Microtubule targeting agents (MTAs) have attracted extensive attention for cancer treatment. However, their clinical efficacies are limited by intolerable toxicities, inadequate efficacy and acquired multidrug resistance. The combination of MTAs with other antineoplastics has become an efficient strategy to lower the toxicities, overcome resistance and improve the efficacies for cancer treatment. In this article, we review the combinations of MTAs with some other anticancer drugs, such as cytotoxic agents, kinases inhibitors, histone deacetylase inhibitors, immune checkpoints inhibitors, to overcome these obstacles. We strongly believe that this review will provide helpful information for combination therapy based on MTAs. 

Combination of microtubule targeting agents with other antineoplastics for cancer treatment

Epigenetic dysregulation plays a crucial role in the development and progression of ovarian cancer. Since the first experiment conducted on resistant ovarian cancer cells using demethylating drugs, multiple clinical trials have revealed that epigenetic targeted drugs combined with chemotherapy, molecular-targeted drugs, or even immunotherapy could enhance tumor sensitivity and reverse acquired resistances. Here, we summarized the combination strategies of epigenetic targeted drugs with other treatment strategies of ovarian cancer and discussed the principles of combination therapy. Finally, we enumerated several reasonable clinical trial designs as well as future drug development strategies, which may provide promising ideas for the application of epigenetic drugs to ovarian cancer. 

Tackling drug resistance in ovarian cancer with epigenetic targeted drugs.

Pan-bromodomain and extra terminal (Pan-BET) inhibitors show profound efficacy but exhibit pharmacology-driven toxicities in clinical trials. The development of domain-selective BET inhibitors to separate efficacy and toxicity is urgently needed. Herein, we report a series of furo[3,2-c]pyridin-4(5H)-one derivatives as novel BD2-selective BET inhibitors. The representative compound 8l (XY153) potently bound to BRD4 BD2 with an half-maximum inhibitory concentration (IC50) value of 0.79 nM and displayed 354-fold selectivity over BRD4 BD1. Besides, 8l exhibited 6-fold BRD4 BD2 domain selectivity over other BET BD2 domains. Compound 8l displayed potent antiproliferative activity against multiple tumor cell lines, especially MV4-11 (IC50 = 0.55 nM), while showing weak cytotoxicity against the normal lung fibroblast cell line. It highlights the safety profile of this series of BD2 inhibitors. 8l also demonstrated good metabolic stability in vitro. These data indicate that 8l may serve as a new and valuable lead compound for the development of potential therapeutics against acute myeloid leukemia (AML).

Structure-Based Discovery and Optimization of Furo[3,2-c]pyridin-4(5H)-one Derivatives as Potent and Second Bromodomain (BD2)-Selective Bromo and Extra Terminal Domain (BET) Inhibitors.

Radiotherapy can induce various adverse effects including fibrosis in cancer patients. Radiation‐induced aberrant expression of profibrotic genes has been associated with dysregulated epigenetic mechanisms. Pan‐BET (bromodomain and extraterminal domain) inhibitors, such as JQ1 and I‐BET151, have been reported to attenuate the profibrotic response after irradiation. Despite their profound preclinical efficacy, the clinical utility of pan‐inhibitors is limited due to observed cytotoxicicities. Recently, inhibitors were developed that selectively target the first (BD1) and second (BD2) bromodomain of the BET proteins (iBET‐BD1 [GSK778] and iBET‐BD2 [GSK046]). Here, their potential to attenuate radiation‐induced fibroblast activation with low‐toxicity was investigated. Our results indicated that cell proliferation and cell cycle progression in fibroblasts from BJ cells and six donors were reduced when treated with I‐BET151 and iBET‐BD1, but not with iBET‐BD2. After irradiation, induction of DGKA and profibrotic markers, especially COL1A1 and ACTA2, was attenuated with all BET inhibitors. H3K27ac enrichment was similar at the DGKA enhancer region after I‐BET151 treatment and irradiation, but was reduced at the COL1A1 transcription start site and the ACTA2 enhancer site. iBET‐BD2 did not change H3K27ac levels in these regions. BRD4 occupancy at these regions was not altered by any of the compounds. Cell migration activity was measured as a characteristic independent of extracellular matrix production and was unchanged in fibroblasts after irradiation and BET inhibitor‐treatment. In conclusion, iBET‐BD2 efficiently suppressed radiation‐induced expression of DGKA and profibrotic markers without showing cytotoxicity. Thus BD2‐selective targeting is a promising new therapeutic avenue for further investigations to prevent or attenuate radiotherapy‐induced fibrosis.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/ijc.33989

Yanzhi Zhang

Papers

Progress in the development of domain selective inhibitors of the bromo and extra terminal domain family (BET) proteins.