PGC-1α repression dysregulates lipid metabolism and induces lipid droplet accumulation in retinal pigment epithelium.

Drusen, the yellow deposits under the retina, are composed of lipids and proteins, and represent a hallmark of age-related macular degeneration (AMD). Lipid droplets are also reported in the retinal pigment epithelium (RPE) from AMD donor eyes. However, the mechanisms underlying these disease phenotypes remain elusive. Previously, we showed that Pgc-1α repression, combined with a high-fat diet (HFD), induce drastic AMD-like phenotypes in mice. We also reported increased PGC-1α acetylation and subsequent deactivation in the RPE derived from AMD donor eyes. Here, through a series of in vivo and in vitro experiments, we sought to investigate the molecular mechanisms by which PGC-1α repression could influence RPE and retinal function. We show that PGC-1α plays an important role in RPE and retinal lipid metabolism and function. In mice, repression of Pgc-1α alone induced RPE and retinal degeneration and drusen-like deposits. In vitro inhibition of PGC1A by CRISPR-Cas9 gene editing in human RPE (ARPE19- PGC1A KO) affected the expression of genes responsible for lipid metabolism, fatty acid ß-oxidation (FAO), fatty acid transport, low-density lipoprotein (LDL) uptake, cholesterol esterification, cholesterol biosynthesis, and cholesterol efflux. Moreover, inhibition of PGC1A in RPE cells caused lipid droplet accumulation and lipid peroxidation. ARPE19-PGC1A KO cells also showed reduced mitochondrial biosynthesis, impaired mitochondrial dynamics and activity, reduced antioxidant enzymes, decreased mitochondrial membrane potential, loss of cardiolipin, and increased susceptibility to oxidative stress. Our data demonstrate the crucial role of PGC-1α in regulating lipid metabolism. They provide new insights into the mechanisms involved in lipid and drusen accumulation in the RPE and retina during aging and AMD, which may pave the way for developing novel therapeutic strategies targeting PGC-1α.

Discovery of a first-in-class degrader for the protein arginine methyltransferase 6 (PRMT6).

PRMT6 is a member of the protein arginine methyltransferase family, which participates in a variety of physical processes and plays an important role in the occurrence and development of tumors. Using small molecules to design and synthesize targeted protein degraders is a new strategy for drug development. Here, we report the first-in-class degrader SKLB-0124 for PRMT6 based on the hydrophobic tagging (HyT) method.Importantly, SKLB-0124 induced proteasome dependent degradation of PRMT6 and significantly inhibited the proliferation of HCC827 and MDA-MB-435 cells. Moreover, SKLB-0124 effectively induced apoptosis and cell cycle arrest in these two cell lines. Our data clarified that SKLB-0124 is a promising selective PRMT6 degrader for cancer therapy which is worthy of further evaluation.

Targeting type I PRMTs as promising targets for the treatment of pulmonary disorders: Asthma, COPD, lung cancer, PF, and PH.

Pulmonary disorders, including asthma, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis (PF), pulmonary hypertension (PH), and lung cancer, seriously impair the quality of lives of patients. A deeper understanding of the occurrence and development of the above diseases may inspire new strategies to remedy the scarcity of treatments. Type I protein arginine methyltransferases (PRMTs) can affect processes of inflammation, airway remodeling, fibroblast proliferation, mitochondrial mass, and epithelial dysfunction through substrate methylation and non-enzymatic activity, thus affecting the occurrence and development of asthma, COPD, lung cancer, PF, and PH. As potential therapeutic targets, inhibitors of type I PRMTs are developed, moreover, representative compounds such as GSK3368715 and MS023 have also been used for early research. Here, we collated structures of type I PRMTs inhibitors and compared their activity. Finally, we highlighted the physiological and pathological associations of type I PRMTs with asthma, COPD, lung cancer, PF, and PH. The developing of type I PRMTs modulators will be beneficial for the treatment of these diseases.

A two-stage partial nitritation-denitritation/anammox (PN-DN/A) process to treat high-solid anaerobic digestion (HSAD) reject water: Verification based on pilot-scale and full-scale projects.

High-solid anaerobic digestion (HSAD) reject water, distinguished by elevated levels of chemical oxygen demand (COD), NH4+-N and an imbalanced COD/TIN, presents a significant challenge for treatment through conventional partial nitritation/ anammox (PN/A) process. This study introduced a revised two-stage PN/A process, namely partial nitritation/denitritation-anammox (PN-DN/A) process. Its effectiveness was investigated through both pilot-scale (12 t/d) and full-scale (400 t/d) operations, showcasing stable operation with an impressive total removal rate of over 90 % for total inorganic nitrogen (TIN) and exceeding 60 % for COD. Notably, 30 % of TIN was eliminated through heterotrophic denitritation in partial nitritation-denitritation (PN-DN) stage, while approximately 55 % of TIN removal occurred in the anammox stage with anaerobic ammonium oxidizing bacteria (AnAOB) enrichment (Candidatus Kuenenia, 25.9 % and 26.6 % relative abundance for pilot and full scale). In the PN-DN stage, aerobic-anaerobic alternation promoted organics elimination (around 50 % COD) and balanced nitrogen species. Microbial and metagenomic analysis verified the coupling between autotrophic and heterotrophic denitritation and demonstrated that PN-DN stage acted as a protective buffer for anammox stage. This comprehensive study highlights the PN-DN/A process's efficacy in stably treating HSAD reject water.

O-GlcNAcylation of MITF regulates its activity and CDK4/6 inhibitor resistance in breast cancer.

Cyclin-dependent kinases 4 and 6 (CDK4/6) play a pivotal role in cell cycle and cancer development. Targeting CDK4/6 has demonstrated promising effects against breast cancer. However, resistance to CDK4/6 inhibitors (CDK4/6i), such as palbociclib, remains a substantial challenge in clinical settings. Using high-throughput combinatorial drug screening and genomic sequencing, we found that the microphthalmia-associated transcription factor (MITF) is activated via O-GlcNAcylation by O-GlcNAc transferase (OGT) in palbociclib-resistant breast cancer cells and tumors; O-GlcNAcylation of MITF at Serine 49 enhanced its interaction with importin α/ß, thus promoting its translocation to nuclei, where it suppressed palbociclib-induced senescence; inhibition of MITF or its O-GlcNAcylation re-sensitized resistant cells to palbociclib. Remarkably, clinical studies confirmed the activation of MITF in tumors from patients who are palbociclib-resistant or undergoing palbociclib treatment. Collectively, our studies shed light on a novel mechanism regulating palbociclib-resistance, and present clinical evidence for developing therapeutic approaches to treat CDK4/6i-resistant breast cancer patients.

Evolution of dissolved organic nitrogen (DON) during sludge reject water treatment revealed by FTICR-MS.

This study evaluated the ability to remove dissolved organic matter (DOM), particularly dissolved organic nitrogen (DON), at a molecular level using Fourier transform ion cyclotron resonance mass spectrometry (FTICR-MS) in a full-scale reject water treatment project comprising three steps of short-cut nitrification and denitrification, two-stage AO, and ultrafiltration membrane system. The results indicated that short-cut nitrification and denitrification were effective in reducing the DON concentration from an average of about 180 mg/L to 43 mg/L. The average molecular weight of DOM showed a decreasing trend from 238 Da to 160 Da. The percentage of nitrogen-containing organic compounds (CHON-DOM), which is the primary component of reject water DOM, increased from 65.79 % to 72.35 %, while the percentage of CHO-DOM decreased from 20.67 % to 15.24 %. The percentage of CHOS-DOM remained stable at 12.21 %-13.54 %. The percentage of protein-DOM decreased from 50.32 % to 18.40 %, while lignin-DOM increased from 36.16 % to 55.88 % and carbohydrate-DOM increased from 2.68 % to 9.74 %. The short-cut nitrification and denitrification and ultrafiltration membrane system both generated more unsaturated, highly aromatic DOM. This study provides insights into the effects of different wastewater treatment processes on the evolution of DOM/DON, which can be useful for effective DON control.

Diaphragmatic ultrasound can help evaluate pulmonary dysfunction in patients with stroke.

Objective: Pulmonary dysfunction after stroke is increasingly gaining attention from clinical and rehabilitation specialists. However, owing to cognitive and motor dysfunction in patients with stroke, determining the pulmonary function of these patients remains challenging. The present study aimed to devise a simple method for an early evaluation of pulmonary dysfunction in patients with stroke. Methods: Overall, 41 patients with stroke in the recovery period (stroke group) and 22 matched healthy controls (control group) were included in the study. We first collected data regarding baseline characteristics for all participants. Furthermore, the participants with stroke were examined using additional scales, such as the National Institutes of Health Stroke Scale (NIHSS), Fugl-Meyer assessment scale (FMA), and modified Barthel Index (MBI). Subsequently, we examined the participants with simple pulmonary function detection and diaphragm ultrasound (B-mode). Ultrasound indices calculated were as follows: the thickness of the diaphragm under the position of functional residual capacity (TdiFRC), the thickness of the diaphragm under the position of forced vital capacity (TdiFVC), thickness fraction, and diaphragmatic mobility. Finally, we compared and analyzed all data to identify group differences, the correlation between pulmonary function and diaphragmatic ultrasound indices, and the correlation between pulmonary function and assessment scale scores in patients with stroke, respectively. Results: Compared with the control group, patients in the stroke group exhibited lower values for indices of pulmonary and diaphragmatic function (p < 0.001), except for TdiFRC (p > 0.05). The majority of the patients with stroke had restrictive ventilatory dysfunction, as indicated by a significantly higher incidence ratio (36 in 41 patients) than that in the control group (0 in 22 patients) (p < 0.001). Moreover, significant correlations were found between pulmonary function and diaphragmatic ultrasound indices (p < 0.05), with the strongest correlation between TdiFVC and pulmonary indices. In the stroke group, pulmonary function indices were negatively correlated with the NIHSS scores (p < 0.001) and positively correlated with the FMA scores (p < 0.001). No (p > 0.05) or weak (p < 0.05) correlation was found between pulmonary function indices and the MBI scores. Conclusion: We found that patients with stroke had pulmonary dysfunction even in the recovery period. Diaphragmatic ultrasound can be used as a simple and effective tool for detecting pulmonary dysfunction in patients with stroke, with TdiFVC being the most effective index.

The Anti-Aging Hormone Klotho Promotes Retinal Pigment Epithelium Cell Viability and Metabolism by Activating the AMPK/PGC-1α Pathway.

Initially discovered by Makuto Kuro-o in 1997, Klotho is a putative aging-suppressor gene when overexpressed and accelerates aging when deleted in mice. Previously, we showed that α-Klotho regulates retinal pigment epithelium (RPE) functions and protects against oxidative stress. However, the mechanisms by which Klotho influences RPE and retinal homeostasis remain elusive. Here, by performing a series of in vitro and in vivo experiments, we demonstrate that Klotho regulates cell viability under oxidative stress, mitochondrial gene expression and activity by inducing the phosphorylation of AMPK and p38MAPK, which in turn phosphorylate and activate CREB and ATF2, respectively, triggering PGC-1α transcription. The inhibition of Klotho in human RPE cells using CRISPR-Cas9 gene editing confirmed that a lack of Klotho negatively affects RPE functions, including mitochondrial activity and cell viability. Proteomic analyses showed that myelin sheath and mitochondrial-related proteins are downregulated in the RPE/retina of Kl-/- compared to WT mice, further supporting our biochemical observations. We conclude that Klotho acts upstream of the AMPK/PGC-1α pathway and regulates RPE/retinal resistance to oxidative stress, mitochondrial function, and gene and protein expressions. Thus, KL decline during aging could negatively impact retinal health, inducing age-related retinal degeneration.

[Advances in the diagnosis and treatment of phosphomannomutase 2 deficiency]. / ç£·é ¸ç”˜éœ²ç³–å˜ä½é ¶2缺乏症的诊治进展.

Phosphomannomutase 2 deficiency is the most common form of N-glycosylation disorders and is also known as phosphomannomutase 2-congenital disorder of glycosylation (PMM2-CDG). It is an autosomal recessive disease with multi-system involvements and is caused by mutations in the PMM2 gene (OMIM: 601785), with varying severities in individuals. At present, there is still no specific therapy for PMM2-CDG, and early identification, early diagnosis, and early treatment can effectively prolong the life span of pediatric patients. This article reviews the advances in the diagnosis and treatment of PMM2-CDG.

Discovery of a Novel Covalent EZH2 Inhibitor Based on Tazemetostat Scaffold for the Treatment of Ovarian Cancer.

Enhancer of zeste homologue 2 (EZH2) is the enzymatic catalytic subunit of polycomb repressive complex 2 (PRC2), which plays an important role in post-translational modifications of histones. In this study, we designed and synthesized a new series EZH2 covalent inhibitors that have rarely been reported. Biochemical studies and mass spectrometry provide information that SKLB-03220 could covalently bind to the S-adenosylmethionine (SAM) pocket of EZH2. Besides, SKLB-03220 was highly potent for EZH2MUT, while exhibiting weak activities against other tested histone methyltransferases (HMTs) and kinases. Moreover, SKLB-03220 displayed noteworthy potency against ovarian cancer cell lines and continuously abolished H3K27me3 after washing out. Furthermore, oral administration of SKLB-03220 significantly inhibited tumor growth in PA-1 xenograft model without obvious adverse effects. Taken together, SKLB-03220 is a potent, selective EZH2 covalent inhibitor with noteworthy anticancer efficacy both in vitro and in vivo.

Event-Triggered Practical Prescribed Time Output Feedback Neuroadaptive Tracking Control Under Saturated Actuation.

This work focuses on the issue of event-triggered practical prescribed time tracking control for a type of uncertain nonlinear systems subject to actuator saturation and unmeasurable states as well as time-varying unknown control coefficients. First, a state observer with simple structure is constructed by means of neural network technology to estimate the unmeasurable system states under time-varying control coefficients. Then, with the help of one-to-one nonlinear mapping of the tracking error, an event-triggered output feedback control scheme is developed to steer the tracking error into a residual set of predefined accuracy within a preassigned settling time. Unlike existing related control methods, there is no need to involve finite-time state observer or fractional power feedback of system states, and thus, the control solution presented here is less complex and more acceptable. The key technique in control design lies in the establishment of an alternative first-order auxiliary system for dealing with the impact arisen from the input saturation. In our proposed approach, a new bounded function related to auxiliary variable and new dynamics of the auxiliary system are skillfully utilized such that the upper bound of the difference between actual input and designed input signal is not involved in implementation of the controller.

Prescribed Performance Tracking Control Under Uncertain Initial Conditions: A Neuroadaptive Output Feedback Approach.

This work is concerned with the prescribed performance tracking control for a family of nonlinear nontriangular structure systems under uncertain initial conditions and partial measurable states. By combining neural network and variable separation technique, a state observer with a simple structure is constructed for output-based finite-time tracking control, wherein the issue of algebraic loop arising from a nontriangular structure is circumvented. Meanwhile, by using an error transformation, the developed control scheme is able to ensure tracking with a prescribed accuracy within a pregiven time at a preassigned convergence rate under any bounded initial condition, eliminating the long-standing initial condition dependence issue inherited with conventional prescribed performance control methods, and guaranteeing the predeterminability of convergence time simultaneously. Two simulation examples also demonstrate the effectiveness of the presented control strategy.

Design and Synthesis of Fibroblast Growth Factor Receptor (FGFR) and Histone Deacetylase (HDAC) Dual Inhibitors for the Treatment of Cancer.

The activation of the STAT signal after incubation with the HDAC inhibitor represents a key mechanism causing resistance to HDAC inhibitors in some solid tumor cells, while the FGFR inhibitor could downregulate the level of pSTAT3. Inspired by the therapeutic prospect of FGFR/HDAC dual inhibitors, we designed and synthesized a series of quinoxalinopyrazole hydroxamate derivatives as FGFR/HDAC dual inhibitors. Among them, compound 10e potently inhibited FGFR1-4 and HDAC1/2/6/8 and presented improved antiproliferative effects of tumor cells. Further studies indicated that 10e also downregulated the expression of pSTAT3, potentially overcoming resistance to HDAC inhibitors. What's more, 10e significantly inhibited the tumor growth in HCT116 and SNU-16 xenograft models with favorable pharmacokinetic profiles. Collectively, these results supported that 10e could be a new drug candidate for malignant tumors.

A novel fixed-dose combination treatment for chronic hepatitis C, based on NS5A inhibitor fopitasvir and NS5B inhibitor sofosbuvir.

Drug resistance caused by the extreme genetic variability of zhe hepatitis C virus has rendered effective combinations of drugs indispensable in the treatment of chronic hepatitis C (CHC). Herein, we developed a fixed-dose combination (FDC) treatment containing the NS5B inhibitor sofosbuvir (SOF) and the NS5A inhibitor fopitasvir (FOP). Then the dissolution behavior of FOP in FOP/SOF FDC was improved by co-micronizing FOP with lactose. The enhanced dissolution rate of FOP in the FDC was in good agreement with the behavior of the FOP singledrug tablet. In addition, pharmacokinetic studies showed that both FOP and SOF in the FDC exhibited similar characteristics (area under the curve, Cmax, Tmax, and T1/2) as those of tablets containing FOP or SOF alone. These results revealed that the FOP/SOF FDC represents a potential therapeutic option for the treatment of CHC.

Synthesis and Biological Evaluation of Novel 4-(4-Formamidophenylamino)-N-methylpicolinamide Derivatives as Potential Antitumor Agents.

A novel series of 4-(4-formamidophenylamino)-N-methylpicolinamide derivatives were synthesized and evaluated against different tumor cell lines. Experiments in vitro showed that these derivatives could inhibit the proliferation of two kinds of human cancer cell lines (HepG2, HCT116) at low micromolar concentrations and the most potent analog 5q possessed broad-spectrum antiproliferative activity. Experiments in vivo demonstrated that 5q could effectively prolong the longevity of colon carcinoma-burdened mice and slow down the progression of cancer cells by suppression of angiogenesis and the induction of apoptosis and necrosis.

Design and Synthesis of EZH2-Based PROTACs to Degrade the PRC2 Complex for Targeting the Noncatalytic Activity of EZH2.

EZH2 mediates both PRC2-dependent gene silencing via catalyzing H3K27me3 and PRC2-independent transcriptional activation in various cancers. Given its oncogenic role in cancers, EZH2 has constituted a compelling target for anticancer therapy. However, current EZH2 inhibitors only target its methyltransferase activity to downregulate H3K27me3 levels and show limited efficacy because of inadequate suppression of the EZH2 oncogenic activity. Therefore, therapeutic strategies to completely block the oncogenic activity of EZH2 are urgently needed. Herein, we report a series of EZH2-targeted proteolysis targeting chimeras (PROTACs) that induce proteasomal degradation of PRC2 components, including EZH2, EED, SUZ12, and RbAp48. Preliminary assessment identified E7 as the most active PROTAC molecule, which decreased PRC2 subunits and H3K27me2/3 levels in various cancer cells. Furthermore, E7 strongly inhibited transcriptional silencing mediated by EZH2 dependent on PRC2 and transcriptional activation mediated by EZH2 independent of PRC2, showing significant antiproliferative activities against cancer cell lines dependent on the enzymatic and nonenzymatic activities of EZH2.

Inhibition of LSD1 promotes the differentiation of human induced pluripotent stem cells into insulin-producing cells.

BACKGROUND: Human induced pluripotent stem cells (hiPSCs) represent a potentially unlimited source of pancreatic endocrine lineage cells. Although insulin-producing ß cells derived from hiPSCs have been successfully induced, much work remains to be done to achieve mature ß cells. Lysine-specific demethylase 1 (LSD1) plays an important role in the regulation of hiPSC self-renewal and differentiation. We propose a new strategy to acquire insulin-producing cells (IPCs) from hiPSCs by knocking down LSD1. METHODS: Knockdown of LSD1 in hiPSCs with five shRNA. Assessment of the effects of shRNA on hiPSC proliferation, cell cycle, and apoptosis. Using knockdown hiPSCs with 31.33% LSD1 activity, we achieved a four-step differentiation into IPCs and test its differentiation efficiency, morphology, and marker genes and proteins. We implanted the IPCs into the renal subcapsular of SCID-Beige diabetic mice to evaluate the hypoglycemic effect in vivo. We tested LSD1 and HDAC1 whether they are present in the CoREST complex through IP-WB, and analyzed LSD1, CoREST, HDAC1, H3K4me2/me3, and H3K27me3 protein expression before and after knockdown of LSD1. RESULTS: Differentiated hiPSCs were 38.32% ± 3.54% insulin-positive cells and released insulin/C-peptide in response to glucose stimulus in a manner comparable to adult human islets. Most of the IPCs co-expressed mature ß cell-specific markers. When transplanted under the left renal capsule of SCID-Beige diabetic mice, these IPCs reversed hyperglycemia, leading to a significant increase in the definitive endoderm cells. IP-WB results showed that LSD1, HDAC1, and CoREST formed a complex in hiPSCs. Chip-PCR results showed that LSD1, HDAC1, and CoREST were enriched in the same district during the SOX17 and FOXA2 promoter region. Inhibition of LSD1 would not affect the level of CoREST but decreased the HDAC1 expressions. The H3K4me2/me3 and H3K9act level of SOX17 and FOXA2 promoter region increased after inhibited of LSD1, and promoted transcriptional activation. The H3K4me2/me3 and H3K9act level of OCT4 and SOX2 promoter region decreased with the transcriptional repressed. CONCLUSIONS: LSD1 regulated histone methylation and acetylation in promoter regions of pluripotent or endodermal genes. Our results suggest a highly efficient approach to producing IPCs from hiPSCs.

Neuroadaptive Control Design for Pure-Feedback Nonlinear Systems: A One-Step Design Approach.

In this article, we propose a one-step control design approach for pure-feedback nonlinear systems in the presence of unmatched and nonvanishing external disturbances. Different from the commonly utilized backstepping design, the proposed method, integrated with the dynamic surface control (DSC) technique, only involves one-step design with one single Lyapunov function in the whole control synthesis, which derives the actual control and the intermediate controls simultaneously in a collective way, avoiding the repetitive design procedures and multiple Lyapunov functions, yet circumventing the issue of "explosion of complexity." Furthermore, with this method, the increase in system order does not increase the design and analysis complexity. Numerical simulation examples confirm and validate the effectiveness of the proposed method.

Molecular characterization of carbapenem-resistant Klebsiella pneumoniae isolates with focus on antimicrobial resistance.

BACKGROUND: The enhancing incidence of carbapenem-resistant Klebsiella pneumoniae (CRKP)-mediated infections in Mengchao Hepatobiliary Hospital of Fujian Medical University in 2017 is the motivation behind this investigation to study gene phenotypes and resistance-associated genes of emergence regarding the CRKP strains. In current study, seven inpatients are enrolled in the hospital with complete treatments. The carbapenem-resistant K. pneumoniae whole genome is sequenced using MiSeq short-read and Oxford Nanopore long-read sequencing technology. Prophages are identified to assess genetic diversity within CRKP genomes. RESULTS: The investigation encompassed eight CRKP strains that collected from the patients enrolled as well as the environment, which illustrate that blaKPC-2 is responsible for phenotypic resistance in six CRKP strains that K. pneumoniae sequence type (ST11) is informed. The plasmid with IncR, ColRNAI and pMLST type with IncF[F33:A-:B-] co-exist in all ST11 with KPC-2-producing CRKP strains. Along with carbapenemases, all K. pneumoniae strains harbor two or three extended spectrum ß-lactamase (ESBL)-producing genes. fosA gene is detected amongst all the CRKP strains. The single nucleotide polymorphisms (SNP) markers are indicated and validated among all CRKP strains, providing valuable clues for distinguishing carbapenem-resistant strains from conventional K. pneumoniae. CONCLUSIONS: ST11 is the main CRKP type, and blaKPC-2 is the dominant carbapenemase gene harbored by clinical CRKP isolates from current investigations. The SNP markers detected would be helpful for characterizing CRKP strain from general K. pneumoniae. The data provides insights into effective strategy developments for controlling CRKP and nosocomial infection reductions.

Design, synthesis and biological evaluation of 3,5-dimethylisoxazole and pyridone derivatives as BRD4 inhibitors.

Bromodomain-containing protein 4 (BRD4), a member of the bromodomain and extra-terminal (BET) family, has been recognized as an attractive candidate target for the treatment targeting gene transcription in several types of cancers. In this study, two types of novel compounds were designed, synthesized and evaluated as BRD4 inhibitors. Therein, pyridone derivatives were more effective against BRD4 protein and human leukemia cell lines MV4-11. Among them, compounds 11d, 11e and 11f were the most potential ones with IC50 values of 0.55 µM, 0.86 µM and 0.80 µM against BRD4, and exhibited remarkable antiproliferative activities against MV4-11 cells with IC50 values of 0.19 µM, 0.32 µM and 0.12 µM, respectively. Moreover, in western blot assay, compound 11e induced down-regulation of C-Myc, which is a significant downstream gene of BRD4. Cell cycle analysis assay also showed that compound 11e could block MV4-11 cells at G0/G1 phase. Taken together, our results suggested that compound 11e and its derivatives were a class of novel structural potential BRD4 inhibitors and could serve as lead compounds for further exploration.