Blocking the interactions between bromodomain and extraterminal (BET) proteins and acetylated lysines of histones by small molecules has important implications for the treatment of cancers and other diseases. Many pan-BET inhibitors have shown satisfactory results in clinical trials, but their potential for poor tolerability and toxicity persist. However, recently reported studies illustrate that some BET bromodomain (BET-BD1 or BET-BD2)-selective inhibitors have advantage over pan-inhibitors, including reduced toxicity concerns. Furthermore, some selective BET inhibitors have similar or even better therapeutic efficacy in inflammatory diseases or cancers. Therefore, the development of selective BET inhibitors has become a hot spot for medicinal chemists. Here, we summarize the known selective BET-BD1 and BET-BD2 inhibitors and review the methods for enhancing the selectivity and potency of these inhibitors based on their different modes of interactions with BET-BD1 or BET-BD2. Finally, we discuss prospective strategies that selectively target the bromodomains of BET proteins.

We herein report the identification, structural optimization, and structure−activity relationship of thieno[2,3d]pyrimidine derivatives as a novel kind of selective vascular endothelial growth factor receptor 3 (VEGFR3) inhibitors. N-(4-Chloro-3-(trifluoromethyl)phenyl)-4-(6-(4-(4-methylpiperazin-1yl)phenyl)thieno[2,3-d]pyrimidin-4-yl)piperazine-1-carboxamide (38k) was the most potent VEGFR3 inhibitor (IC 50 = 110.4 nM) among developed compounds. Compared with VEGFR1 and VEGFR2, VEGFR3 was approximately 100 times more selective. Here, compound 38k significantly inhibited proliferation and migration of VEGF-C-induced human dermal lymphatic endothelial cells (HDLEC), MDA-MB-231, and MDA-MB-436 cells by inactivating the VEGFR3 signaling pathway. Additionally, 38k induced cell apoptosis and a prolonged G1/S-phase in MDA-MB-231 and MDA-MB-436 cells. It also presented acceptable pharmacokinetic characteristics in Sprague-Dawley (SD) rats with an oral bioavailability of 30.9%. In the xenograft model in vivo, 38k effectively inhibited breast cancer growth by suppressing the VEGFR3 signaling pathway. 38k pronouncedly resisted the formation of pulmonary metastatic nodules in mice. Collectively, 38k may be a promising therapeutic agent of metastatic breast cancer.

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Novel carbon nanotubes (CNTs) and hierarchical ZnO mircosphere composites were prepared via a facile chemical deposition route and their photocatalytic performance in degradation of methylene bule (MB) was investigated. The results indicate that as-prepared ZnO/CNTs hierarchical microsphere composite with 1.1 wt% CNTs shows the optimized photocatalytic activity. 10 The photocatalytic performance improvement can be attributed to the triple effects of high surface area, enhanced light absorption and suppression of charge carriers recombination resulting from the interaction between ZnO and CNTs.