ABSTRACT
Ovarian cancer is one of the tumors with the highest fatality rate among gynecological tumors. The current 5-year survival rate of ovarian cancer is <35%. Therefore, more novel alternative strategies and drugs are needed to treat ovarian cancer. The transcription factor B-cell lymphoma 6 (BCL6) is critically associated with poor prognosis and cisplatin resistance in ovarian cancer treatment. Therefore, BCL6 may be an attractive therapeutic target for ovarian cancer. However, the role of targeting BCL6 in ovarian cancer remains elusive. Here, we developed a novel BCL6 small molecule inhibitor, WK369, which exhibits excellent anti-ovarian cancer bioactivity, induces cell cycle arrest and causes apoptosis. WK369 effectively inhibits the growth and metastasis of ovarian cancer without obvious toxicity in vitro and in vivo. meanwhile, WK369 can prolong the survival of ovarian cancer-bearing mice. It is worth noting that WK369 also has significant anti-tumor effects on cisplatin-resistant ovarian cancer cell lines. Mechanistic studies have shown that WK369 can directly bind to the BCL6-BTB domain and block the interaction between BCL6 and SMRT, leading to the reactivation of p53, ATR and CDKN1A. BCL6-AKT, BCL6-MEK/ERK crosstalk is suppressed. As a first attempt, our study demonstrates that targeting BCL6 may be an effective approach to treat ovarian cancer and that WK369 has the potential to be used as a candidate therapeutic agent for ovarian cancer.
Subject(s)
Cisplatin , Ovarian Neoplasms , Humans , Female , Animals , Mice , Cisplatin/pharmacology , Cisplatin/therapeutic use , Proto-Oncogene Proteins c-bcl-6/genetics , Proto-Oncogene Proteins c-bcl-6/metabolism , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/pathology , Transcription Factors , Cell Line, TumorABSTRACT
The transcription factor B cell lymphoma 6 (BCL6) is an oncogenic driver of diffuse large B cell lymphoma (DLBCL) and mediates lymphomagenesis through transcriptional repression of its target genes by recruiting corepressors to its N-terminal broad-complex/tramtrack/bric-a-brac (BTB) domain. Blocking the protein-protein interactions of BCL6 and its corepressors has been proposed as an effective approach for the treatment of DLBCL. However, BCL6 inhibitors with excellent drug-like properties are rare. Hence, the development of BCL6 inhibitors is worth pursuing. We screened our internal chemical library by luciferase reporter assay and Homogenous Time Resolved Fluorescence (HTRF) assay and a small molecule compound named WK500B was identified. WK500B engaged BCL6 inside cells, blocked BCL6 repression complexes, reactivated BCL6 target genes, killed DLBCL cells and caused apoptosis as well as cell cycle arrest. In animal models, WK500B inhibited germinal center (GC) formation and DLBCL tumour growth without toxic and side effects. Moreover, WK500B displayed strong efficacy and favourable pharmacokinetics and presented superior druggability. Therefore, WK500B is a promising candidate that could be developed as an effective orally available therapeutic agent for DLBCL.
Subject(s)
Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-bcl-6/antagonists & inhibitors , Animals , Apoptosis/drug effects , Cell Cycle/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Synergism , Genes, Reporter , Germinal Center/drug effects , Germinal Center/immunology , Germinal Center/metabolism , Humans , Lymphoma, Large B-Cell, Diffuse , Mice , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/chemistry , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
Combined pollution in groundwater has become increasingly serious. Adding emulsified vegetable oil to an aquifer is an effective method to remediate multiple pollutants. However, the efficiency and threshold values for the remediation of groundwater contaminated by both nitrate and hexavalent chromium (Cr(VI)) stimulated by emulsified vegetable oil remain unclear. In this study, emulsified vegetable oil was used for the first time to simultaneously remediate nitrate and Cr(VI) in groundwater. The results suggested that the addition of emulsified vegetable oil could effectively remediate nitrate and Cr(VI), and there were interplay effects between nitrate and Cr(VI). Nitrate promoted Cr(VI) removal, while Cr(VI) inhibited nitrate reduction. The remediation thresholds for nitrate and Cr(VI) alone were 1600 mg/L and 10 mg/L, respectively (emulsified vegetable oil = 7 g/L). For combined pollution, the remediation threshold values were 868.10 mg/L for nitrate and 12.43 mg/L for Cr(VI) (emulsified vegetable oil = 7 g/L). The dose of emulsified vegetable oil played an important role in the threshold value. When the concentration of emulsified vegetable oil was 10.8 g/L, the maximum threshold values were 1379.79 mg/L for nitrate and 12.67 mg/L for Cr(VI). When the pollutant concentration was below the threshold value, the contaminant could be completely removed.
Subject(s)
Groundwater , Water Pollutants, Chemical , Chromium/analysis , Iron , Nitrates , Plant Oils , Water Pollutants, Chemical/analysisABSTRACT
The transcriptional repressor B-cell lymphoma 6 (BCL6) is frequently misregulated in diffuse large B-cell lymphoma (DLBCL) and has emerged as an attractive drug target for the treatments of lymphoma. In this article, a series of N-phenyl-4-pyrimidinamine derivatives were designed and synthesized as potent BCL6 inhibitors by optimizing hit compound N4-(3-chloro-4-methoxyphenyl)-N2-isobutyl-5-fluoro-2,4-pyrimidinediamine on the basis of the structure-activity relationship. Among them, compound 14j displayed the most potent activities, which significantly blocked the interaction of BCL6 with its corepressors, reactivated BCL6 target genes in a dose-dependent manner, and had better effects compared with the two positive controls. Further studies indicated that a low dose of 14j could effectively inhibit germinal center formation. More importantly, 14j not only showed potent inhibition of DLBCL cell proliferation in vitro but also strongly suppressed the growth of DLBCL in vivo.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Lymphoma, Large B-Cell, Diffuse/drug therapy , Proto-Oncogene Proteins c-bcl-6/antagonists & inhibitors , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Animals , Apoptosis/drug effects , Cell Proliferation , Dose-Response Relationship, Drug , Epigenetic Repression/drug effects , Germinal Center/drug effects , HEK293 Cells , Humans , Male , Mice , Mice, Inbred C57BL , Models, Molecular , Molecular Docking Simulation , Proto-Oncogene Proteins c-bcl-6/genetics , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
Several 6-substituted tetrahydrocarbazole derivatives were designed, synthesized and evaluated for the antibacterial activities against Staphylococcus aureus Newman strain. Subsequently, 2,4-diaminopyrimidine scaffold was merged with the tetrahydrocarbazole unit to generate a series of novel hybrid derivatives and the antibacterial activities were also investigated. Among these novel hybrids, compound 12c showed the most potent activity with a MIC of 0.39-0.78⯵g/mL against S. aureus Newman and Escherichia coli AB1157 strain. In addition, compound 12c exhibited low MIC values against a panel of multidrug-resistant strains of S. aureus.
