Inhibition of SIRT7 overcomes sorafenib acquired resistance by suppressing ERK1/2 phosphorylation via the DDX3X-mediated NLRP3 inflammasome in hepatocellular carcinoma.

AIMS: Sirtuin 7 (SIRT7) plays an important role in tumor development, and has been characterized as a potent regulator of cellular stress. However, the effect of SIRT7 on sorafenib acquired resistance remains unclear and a possible anti-tumor mechanism beyond this process in HCC has not been clarified. We examined the therapeutic potential of SIRT7 and determined whether it functions synergistically with sorafenib to overcome chemoresistance. METHODS: Cancer Genome Atlas-liver HCC data and unbiased gene set enrichment analyses were used to identify SIRT7 as a potential effector molecule in sorafenib acquired resistance. Two types of SIRT7 chemical inhibitors were developed to evaluate its therapeutic properties when synergized with sorafenib. Mass spectrometry was performed to discover a direct target of SIRT7, DDX3X, and DDX3X deacetylation levels and protein stability were explored. Moreover, an in vivo xenograft model was used to confirm anti-tumor effect of SIRT7 and DDX3X chemical inhibitors combined with sorafenib. RESULTS: SIRT7 inhibition mediated DDX3X depletion can re-sensitize acquired sorafenib resistance by disrupting NLRP3 inflammasome assembly, finally suppressing hyperactive ERK1/2 signaling in response to NLRP3 inflammasome-mediated IL-1ß inhibition. CONCLUSIONS: SIRT7 is responsible for sorafenib acquired resistance, and its inhibition would be beneficial when combined with sorafenib by suppressing hyperactive pro-cell survival ERK1/2 signaling.

Crystal structure of [1,2,4]triazolo[4,3-b]pyridazine derivatives as BRD4 bromodomain inhibitors and structure-activity relationship study.

BRD4 contains two tandem bromodomains (BD1 and BD2) that recognize acetylated lysine for epigenetic reading, and these bromodomains are promising therapeutic targets for treating various diseases, including cancers. BRD4 is a well-studied target, and many chemical scaffolds for inhibitors have been developed. Research on the development of BRD4 inhibitors against various diseases is actively being conducted. Herein, we propose a series of [1,2,4]triazolo[4,3-b]pyridazine derivatives as bromodomain inhibitors with micromolar IC50 values. We characterized the binding modes by determining the crystal structures of BD1 in complex with four selected inhibitors. Compounds containing [1,2,4] triazolo[4,3-b]pyridazine derivatives offer promising starting molecules for designing potent BRD4 BD inhibitors.

Discovery of BET specific bromodomain inhibitors with a novel scaffold.

Bromodomain and extra-terminal domain (BET) proteins have been considered as potent candidates for anti-cancer drug development. As epigenetic readers, they modulate gene expression by recognizing acetylated lysine residues on histones. Therefore, the pharmacological inhibition of BET proteins has been extensively studied. Herein, we report the novel chemical scaffold of N-(pyridin-2-yl)-1H-benzo[d][1,2,3]triazol-5-amine as BET inhibitors using high-throughput screening assay. Through the analysis of structure-activity relationships, we developed a potent novel compound, which exhibited a better IC50 value about 2-fold compared to iBet762 against the BRD4 bromodomain (BD). The addition of a sulfonyl group to the pyridine ring enhanced the inhibitory activity. Structural studies showed a clear electron density map for the inhibitor and revealed the structural basis for the critical role of the sulfonyl group in the interaction with BRD4.

PCW-1001, a Novel Pyrazole Derivative, Exerts Antitumor and Radio-Sensitizing Activities in Breast Cancer.

As pyrazole and its derivatives have a wide range of biological activities, including anticancer activity, the design of novel pyrazole derivatives has emerged as an important research field. This study describes a novel pyrazole derivative that exerts antitumor and radiosensitizing activities in breast cancer both in vitro and in vivo. We synthesized a novel pyrazole compound N,N-dimethyl-N'-(3-(1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)phenyl)azanesulfonamide (PCW-1001) and showed that it inhibited several oncogenic properties of breast cancer both in vitro and in vivo. PCW-1001 induced apoptosis in several breast cancer cell lines. Transcriptome analysis of PCW-1001-treated cells showed that it regulates genes involved in the DNA damage response, suggesting its potential use in radiotherapy. Indeed, PCW-1001 enhanced the radiation sensitivity of breast cancer cells by modulating the expression of DNA damage response genes. Therefore, our data describe a novel pyrazole compound, PCW-1001, with antitumor and radiosensitizer activities in breast cancer.