Synthetic Routes and Clinical Application of Representative Small-Molecule EGFR Inhibitors for Cancer Therapy.

The epidermal growth factor receptor (EGFR) plays a pivotal role in cancer therapeutics, with small-molecule EGFR inhibitors emerging as significant agents in combating this disease. This review explores the synthesis and clinical utilization of EGFR inhibitors, starting with the indispensable role of EGFR in oncogenesis and emphasizing the intricate molecular aspects of the EGFR-signaling pathway. It subsequently provides information on the structural characteristics of representative small-molecule EGFR inhibitors in the clinic. The synthetic methods and associated challenges pertaining to these compounds are thoroughly examined, along with innovative strategies to overcome these obstacles. Furthermore, the review discusses the clinical applications of FDA-approved EGFR inhibitors such as erlotinib, gefitinib, afatinib, and osimertinib across various cancer types and their corresponding clinical outcomes. Additionally, it addresses the emergence of resistance mechanisms and potential counterstrategies. Taken together, this review aims to provide valuable insights for researchers, clinicians, and pharmaceutical scientists interested in comprehending the current landscape of small-molecule EGFR inhibitors.

Two new triterpenoid saponins and two new goodyerosides isolated from the whole plant of Tournefortia sibirica.

Two new triterpenoid saponins (oleanolic acid 2ß-hydroxyl-3-O-ß-D-glucuronopyranoside-6'-O-buthyl ester (1) and oleanolic acid 2ß-hydroxyl-3-O-[ß-D-glucuronopyranosyl-6'-O-methylester]-28-O-ß-D-glucopyranoside (2)) and two new goodyerosides (4-methylenefuran-2(5H)-one (6'-O-vanilloyl)-ß-D-glucopyranoside (3), 3-hydroxy-2(5H)-furanone, 4-(6'-O-vanilloyl)-ß-D-glucopyranoside (4)), together with seven known compounds (5-11) were isolated from the whole plant of Tournefortia sibirica L. The chemical structures of the compounds were determined by spectroscopic analysis (1D and 2D NMR) and HR-ESI-MS. Compounds 1, 6 and 9 showed significant cytotoxicity towards A549, SK-Hep1 and HeLa cells, with IC50 values ranging from 1.68 ± 0.09 to 6.87 ± 0.13 µM.

METTL14 promotes neuroblastoma formation by inhibiting YWHAH via an m6A-YTHDF1-dependent mechanism.

Neuroblastoma (NB) is a common childhood tumor with a high incidence worldwide. The regulatory role of RNA N6-methyladenosine (m6A) in gene expression has attracted significant attention, and the impact of methyltransferase-like 14 (METTL14) on tumor progression has been extensively studied in various types of cancer. However, the specific influence of METTL14 on NB remains unexplored. Using data from the Target database, our study revealed significant upregulation of METTL14 expression in high-risk NB patients, with strong correlation with poor prognosis. Furthermore, we identified ETS1 and YY1 as upstream regulators that control the expression of METTL14. In vitro experiments involving the knockdown of METTL14 in NB cells demonstrated significant inhibition of cell proliferation, migration, and invasion. In addition, suppressing METTL14 inhibited NB tumorigenesis in nude mouse models. Through MeRIP-seq and RNA-seq analyses, we further discovered that YWHAH is a downstream target gene of METTL14. Mechanistically, we observed that methylated YWHAH transcripts, particularly those in the 5' UTR, were specifically recognized by the m6A "reader" protein YTHDF1, leading to the degradation of YWHAH mRNA. Moreover, the downregulation of YWHAH expression activated the PI3K/AKT signaling pathway, promoting NB cell activity. Overall, our study provides valuable insights into the oncogenic effects of METTL14 in NB cells, highlighting its role in inhibiting YWHAH expression through an m6A-YTHDF1-dependent mechanism. These findings also suggest the potential utility of a biomarker panel for prognostic prediction in NB patients.

Improvement of ribonucleic acid production in Cyberlindnera jadinii and optimization of fermentation medium.

To enhance the ribonucleic acid (RNA) productivity for industrial applications, this study employed strain screening and medium optimization to improve the content of RNA in Cyberlindnera jadinii. A rapid screening method, combining atmospheric and room temperature plasma mutagenesis, 48-deep-well plates fermentation, and microplate reader detection, was developed. A mutant strain named WB15 with high RNA content was successfully obtained, exhibiting the RNA content of 156 ± 4.5 mg/g DCW, 1.4 times of the starting strain CCTCC AY 92020. Furthermore, Plackett-Burman design and response surface methodology were employed to identify three significant factors (yeast extract, soybean peptone, and KH2PO4) affecting the RNA content. By utilizing the optimal medium composed of 13.43 g/L yeast extract, 12.12 g/L soybean peptone and 2.78 g/L KH2PO4, the RNA content of WB15 further increased to 184 ± 4.9 mg/g DCW. Additionally, the mutant strain WB15 exhibited a greater cellular width compared to AY 92020, along with increased growth rate and single-cell RNA content by 22% and 48.9%, respectively. Perturbations in ribosome assembly, specifically a reduction in the ratio of ribosomal proteins to ribosomal RNA of the large subunit, might indirectly contribute to the higher RNA content in the WB15 strain. Overall, the combination of rapid screening with fermentation medium optimization proved to be an effective approach for improving the RNA content of C. jadinii, thus facilitating the industrial production of RNA.

Synthesis of hierarchical mordenite by solvent-free method for dimethyl ether carbonylation reaction.

A series of hierarchical mordenite (MOR) catalysts were synthesized by adding soft templates via the solvent-free method. The influence of different kinds of soft templates on the structure, morphology and acid sites of mordenite were systematically characterized. The characterization results revealed that the addition of soft templates could successfully introduce hierarchical structure into the system while maintaining good crystallinity. The specific surface area and pore volume became larger. Surfactants could also affect the amount and distribution of acid sites, which in turn would affect the dimethyl ether carbonylation activity. Compared with cationic and nonionic surfactants, the addition of anionic surfactants such as sodium dodecyl benzene sulfonate could result in more Al species to preferentially enter into the 8 member ring, thus enhancing the amount of active sites for the carbonylation reaction while weakening the strength. Meanwhile, the addition of sodium dodecyl benzene sulfonate could also reduce the number of strong acid sites in the 12 member ring and obviously improve the carbonylation performance.

Synthesis and clinical application of new drugs approved by FDA in 2023.

In 2023, the U.S. Food and Drug Administration (FDA) granted approval to a total of 55 new drugs, comprising 29 new chemical entities (NCEs) and 25 new biological entities (NBEs). These drugs primarily focus on oncology, the central nervous system, anti-infection, hematology, cardiovascular, ophthalmology, immunomodulatory and other therapeutic areas. Out of the 55 drugs, 33 (60 %) underwent an accelerated review process and received approval, while 25 (45 %) were specifically approved for the treatment of rare diseases. The purpose of this review is to provide an overview of the clinical uses and production techniques of 29 newly FDA-approved NCEs in 2023. Our intention is to offer a comprehensive understanding of the synthetic approaches employed in the creation of these drug molecules, with the aim of inspiring the development of novel, efficient, and applicable synthetic methodologies.

Identification of potential biomarkers in the peripheral blood of neonates with bronchopulmonary dysplasia using WGCNA and machine learning algorithms.

Bronchopulmonary dysplasia (BPD) is often seen as a pulmonary complication of extreme preterm birth, resulting in persistent respiratory symptoms and diminished lung function. Unfortunately, current diagnostic and treatment options for this condition are insufficient. Hence, this study aimed to identify potential biomarkers in the peripheral blood of neonates affected by BPD. The Gene Expression Omnibus provided the expression dataset GSE32472 for BPD. Initially, using this database, we identified differentially expressed genes (DEGs) in GSE32472. Subsequently, we conducted gene set enrichment analysis on the DEGs and employed weighted gene co-expression network analysis (WGCNA) to screen the most relevant modules for BPD. We then mapped the DEGs to the WGCNA module genes, resulting in a gene intersection. We conducted detailed functional enrichment analyses on these overlapping genes. To identify hub genes, we used 3 machine learning algorithms, including SVM-RFE, LASSO, and Random Forest. We constructed a diagnostic nomogram model for predicting BPD based on the hub genes. Additionally, we carried out transcription factor analysis to predict the regulatory mechanisms and identify drugs associated with these biomarkers. We used differential analysis to obtain 470 DEGs and conducted WGCNA analysis to identify 1351 significant genes. The intersection of these 2 approaches yielded 273 common genes. Using machine learning algorithms, we identified CYYR1, GALNT14, and OLAH as potential biomarkers for BPD. Moreover, we predicted flunisolide, budesonide, and beclomethasone as potential anti-BPD drugs. The genes CYYR1, GALNT14, and OLAH have the potential to serve as diagnostic biomarkers for BPD. This may prove beneficial in clinical diagnosis and prevention of BPD.

Harmonizing the craft of crafting clinically endorsed small-molecule BCR-ABL tyrosine kinase inhibitors for the treatment of hematological malignancies.

The advancement and practical use of small-molecule tyrosine kinase inhibitors (TKIs) that specifically target the BCR-ABL fusion protein have introduced a revolutionary era of precision medicine for the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). This review offers a comprehensive exploration of the synthesis, mechanisms of action, and clinical implementation of clinically validated TKIs in the context of BCR-ABL, emphasizing the remarkable strides made in achieving therapeutic precision. We delve into the intricate design and synthesis of these small molecules, highlighting the synthetic strategies and modifications that have led to increased selectivity, enhanced binding affinities, and reduced off-target effects. Additionally, we discuss the structural biology of BCR-ABL inhibition and how it informs drug design. The success of these compounds in inhibiting aberrant kinase activity is a testament to the meticulous refinement of the synthetic process. Furthermore, this review provides a detailed analysis of the clinical applications of these TKIs, covering not only their efficacy in achieving deep molecular responses but also their impact on patient outcomes, safety profiles, and resistance mechanisms. We explore ongoing research efforts to overcome resistance and enhance the therapeutic potential of these agents. In conclusion, the synthesis and utilization of clinically validated small-molecule TKIs targeting BCR-ABL exemplify the transformative power of precision medicine in the treatment of hematological malignancies. This review highlights the evolving landscape of BCR-ABL inhibition and underscores the continuous commitment to refining and expanding the therapeutic repertoire for these devastating diseases.

Progress in the application of dual-energy CT in pancreatic diseases.

Pancreatic diseases are difficult to diagnose due to their insidious onset and complex pathophysiological developmental characteristics. In recent years, dual-energy computed tomography (DECT) imaging technology has rapidly advanced. DECT can quantitatively extract and analyze medical imaging features and establish a correlation between these features and clinical results. This feature enables the adoption of more modern and accurate clinical diagnosis and treatment strategies for patients with pancreatic diseases so as to achieve the goal of non-invasive, low-cost, and personalized treatment. The purpose of this review is to elaborate on the application of DECT for the diagnosis, biological characterization, and prediction of the survival of patients with pancreatic diseases (including pancreatitis, pancreatic cancer, pancreatic cystic tumor, pancreatic neuroendocrine tumor, and pancreatic injury) and to summarize its current limitations and future research prospects.

Gut microbiota-derived tryptophan metabolites alleviate liver injury via AhR/Nrf2 activation in pyrrolizidine alkaloids-induced sinusoidal obstruction syndrome.

BACKGROUND AND AIMS: Hepatic sinusoidal obstruction syndrome (HSOS) is caused by toxic injury, such as pyrrolizidine alkaloids, to the liver sinusoidal endothelial cells, and the gut microbiota may be involved. However, the specific role and underlying mechanism of gut microbiota in HSOS is unknown. METHODS: HSOS model was established by gavage of monocrotaline (MCT) in rats. Fecal microbiota transplantation (FMT) with HSOS-derived or healthy gut flora was also conducted to validate the role of gut microflora in MCT-induced liver injury. The microbial 16 s rRNA analysis and untargeted metabolomics analysis in the faeces were performed to identify HSOS-related flora and metabolites. Finally, by supplementation with specific tryptophan metabolites, such as indole-3-acetaldehyde (IAAld) and indole acetic acid (IAA), we further confirmed the role of tryptophan metabolism in HSOS and the role of the AhR/Nrf2 pathway in MCT-induced liver injury. RESULTS: MCT induced HSOS-like liver injury in rats with significantly altered gut microbiota. Particularly, some tryptophan-metabolizing bacteria reduced in MCT-treated rats, such as Bacteroides, Bifidobacterium, Lactobacillus and Clostridium, and accompanied by a decrease in microbial tryptophan metabolic activity and a series of tryptophan derivatives. Restoring the gut microbiota via FMT improved MCT-induced liver damage, while HSOS-derived gut microbiota aggravated the liver injury induced by MCT. Supplementation with microbial tryptophan derivatives (IAAld or IAA), or 6-formylindolo(3,2-b)carbazole (Ficz, an AhR agonist) could activate the AhR/Nrf2 signaling pathway, thereby attenuating the MCT-induced liver oxidative stress and liver sinusoidal endothelial cells injury. CONCLUSIONS: Gut microbiota plays a critical role in MCT-induced HSOS, with inadequate microbial tryptophan metabolism in the gut and consequently a lower activity of the AhR/Nrf2 signaling pathway in the liver, which should be a potential target for the management of HSOS.

Facilitate or Diminish? Mechanisms of Perceived Organizational Support on Employee Experience of New Generation Employees.

The new generation of employees has emerged as a major force in the labor market, and their employee experience has become a significant factor in transforming the employment relationship. The objective of this study is to see if perceived organizational support influences the employee experience of the new generation of employees. Also, considering that the underlying mechanisms between the two are unclear, this study explores the mediating role of proactive personality and the moderating role of emotional exhaustion. This study used the Perceived Organizational Support Scale, Employee Experience Scale, Proactive Personality Scale, and Emotional Exhaustion Scale to survey 550 new-generation employees in China. The results showed that: perceived organizational support facilitated the level of employee experience of new generation employees; proactive personality partially mediated the relationship between perceived organizational support and employee experience. In addition, emotional exhaustion moderated the relationship between perceived organizational support and proactive personality. This study reveals the mechanisms of organizational and individual factors on the employee experience of new generation employees, explores the growth path of employee experience of new generation employees, and provides insights into the management practice work of business leaders.

High visual perceptual load reduces prepulse inhibition induced by task-unrelated and task-related sound.

Prepulse inhibition (PPI) is an automatic and pre-attentive sensorimotor gating process. Several studies have shown that advanced cognitive functions can modulate PPI. This study aimed to further elucidate the modulatory effect of attentional resource allocation on PPI. We examined the differences in PPI between high and low attentional loads. First, we verified that the adapted feature versus combination visual search paradigm could produce high and low perceptual load differences according to the task demands. Second, we measured the participants' task-unrelated PPI during the visual search task and found that the PPI in the high-load condition was significantly lower than that in the low-load condition. To further elucidate the role of attentional resources, we tested task-related PPI using a dual-task paradigm in which participants were instructed to complete a visual task with an auditory discrimination task. We found a result similar to that of the task-unrelated experiment. The participants in the high-load condition had less PPI than those in the low-load condition. Finally, we ruled out the possibility that the working memory load explains the modulation of PPI. In line with the theory of PPI modulation, these results suggest that allocating limited attentional resources to the prepulse modulates PPI. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Modulating phenylalanine metabolism by L. acidophilus alleviates alcohol-related liver disease through enhancing intestinal barrier function.

BACKGROUND: Impaired metabolic functions of gut microbiota have been demonstrated in alcohol-related liver disease (ALD), but little is known about changes in phenylalanine metabolism. METHODS: Bacterial genomics and fecal metabolomics analysis were used to recognize the changes of phenylalanine metabolism and its relationship with intestinal flora. Intestinal barrier function was detected by intestinal alkaline phosphatase (IAP) activity, levels of tight junction protein expression, colonic inflammation and levels of serum LPS. Lactobacillus acidophilus was chosen to correct phenylalanine metabolism of ALD mice by redundancy analysis and Pearson correlation analysis. RESULTS: Using 16S rRNA sequencing and ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) methods, we identified elevated levels of phenylalanine and its' metabolites in the gut of alcohol-fed mice compared to control mice and were negatively correlated with the abundance of Lactobacillus, which mainly metabolized phenylalanine. The intestinal phenylalanine level was positively correlated with the colon inflammatory factors TNF-α and IL-6, and negatively correlated with ZO-1 and Occludin. While intestinal alkaline phosphatase (IAP) activity was negatively correlated with the colon inflammatory factors TNF-α, IL-6 and MCP-1, and positively correlated with ZO-1 and Occludin. Increased phenylalanine inhibited IAP activity, blocked LPS dephosphorylation, increased colonic inflammation and bacterial translocation. Phenylalanine supplementation aggravated alcohol-induced liver injury and intestinal barrier dysfunction. Among the 37 Lactobacillus species, the abundance of Lactobacillus acidophilus was most significantly decreased in ALD mice. Supplementation with L. acidophilus recovered phenylalanine metabolism and protected mice from alcohol-induced steatohepatitis. CONCLUSIONS: Recovery of phenylalanine metabolism through the oral supplementation of L. acidophilus boosted intestinal barrier integrity and ameliorated experimental ALD.

Change in onset age of first primary colorectal cancer in the USA.

PURPOSE: Identifying the onset age of cancer is essential for its early intervention. The aim of this study was to characterize the features and investigate the variation tendency of first primary colorectal cancer (CRC) onset age in the USA. METHODS: For this retrospective population-based cohort analysis, data on patients diagnosed with first primary CRC (n = 330,977) between 1992 and 2017 were obtained from the Surveillance, Epidemiology, and End Results dataset. Annual percent changes (APC) and average APCs were calculated to examine the changes in average age at CRC diagnosis using the Joinpoint Regression Program. RESULTS: From 1992 to 2017, the average age at CRC diagnosis decreased from 67.0 to 61.2 years, declining by 0.22% and 0.45% annually before and after 2000. The age at diagnosis was lower in the distal than in the proximal CRC cases and the age has the downward trends in all subgroups of sex, race, and stage. Over one-fifth of CRC patients were initially diagnosed with distantly metastatic CRC, with the age lower than that in localized CRC cases (63.5 vs 64.8 years). CONCLUSIONS: The first primary CRC onset age has decreased significantly in the USA over the last 25 years and the modern lifestyle may be responsible for the decline. Specifically, the age of proximal CRC is invariably higher than that of distal CRC. Moreover, the age of advanced stage is lower than that of the early stage. Clinicians should adopt earlier screening age and more effective screening techniques for CRC.

Cytosolic and mitochondrial ribosomal proteins mediate the locust phase transition via divergence of translational profiles.

The phase transition from solitary to gregarious locusts is crucial in outbreaks of locust plague, which threaten agricultural yield and food security. Research on the regulatory mechanisms of phase transition in locusts has focused primarily on the transcriptional or posttranslational level. However, the translational regulation of phase transition is unexplored. Here, we show a phase-dependent pattern at the translation level, which exhibits different polysome profiles between gregarious and solitary locusts. The gregarious locusts exhibit significant increases in 60S and polyribosomes, while solitary locusts possess higher peaks of the monoribosome and a specific "halfmer." The polysome profiles, a molecular phenotype, respond to changes in population density. In gregarious locusts, ten genes involved in the cytosolic ribosome pathway exhibited increased translational efficiency (TE). In solitary locusts, five genes from the mitochondrial ribosome pathway displayed increased TE. The high expression of large ribosomal protein 7 at the translational level promotes accumulation of the free 60S ribosomal subunit in gregarious locusts, while solitary locusts employ mitochondrial small ribosomal protein 18c to induce the assembly of mitochondrial ribosomes, causing divergence of the translational profiles and behavioral transition. This study reveals the translational regulatory mechanism of locust phase transition, in which the locusts employ divergent ribosome pathways to cope with changes in population density.

Simulated wrapped phase optimizes phase retrieval in phase-shifting interferometry.

Phase retrieval is crucial in phase-shifting interferometry and other phase measurement techniques. However, in noisy wrapped phase maps with high steepness, discontinuities arise and cause phase unwrapping errors. To solve this problem, this Letter presents a phase retrieval method based on a simulated wrapped phase. By establishing the correspondence between the simulated and measured interferograms, the difference in wrapped phases between them can be obtained. The difference in wrapped phase map, which has sparse and wide interference fringes, has a higher reliability of phase unwrapping. The proposed method not only possesses high phase retrieval accuracy but it also simplifies the processing of interferograms. Furthermore, the layout of all interferometric systems, the parameters of optical components, and the model of the measured object are known, so the proposed method can be used as a reference for phase retrieval.

Negative emotion-conditioned prepulse induces the attentional enhancement of prepulse inhibition in humans.

Prepulse inhibition (PPI) is a reduction of the acoustic startle reflex (ASR) when the startling stimulus is preceded by a weaker and non-startling stimulus (i.e., prepulse). Previous studies have revealed that PPI can be top-down modulated by selective attention to the fear-conditioned prepulse in animals. However, few researchers have tested this assumption in humans. Thus, in this study, the negative emotional-conditioned prepulse (CS+) was used to explore whether it could improve participants' attention, and further improve the PPI. The results showed that the CS+ prepulse increased the PPI only in females, PPI produced by CS+ prepulse was larger in females than in males, and the perceptual spatial attention further improved the PPI in both females and males. The results suggested that the PPI was affected by emotional, perceptual spatial attention, and sex. These findings highlight an additional method to measure top-down attentional regulation of PPI in humans. Which may offer a useful route to enhance the diagnosis of affective disorders, such as anxiety, depression, and post-traumatic stress disorder.

Zhizhu Kuanzhong, a traditional Chinese medicine, alleviates gastric hypersensitivity and motor dysfunction on a rat model of functional dyspepsia.

Ethnopharmacological relevance: Zhizhu Kuanzhong (ZZKZ) is a traditional Chinese medicine modified from classic formula Zhizhu decoction in "Synopsis of Golden Chamber" (Han Dynasty in the 3rd century) and the Zhizhu pill in "Differentiation on Endogenous" in Jin Dynasty (1,115-1,234). ZZKZ contains four botanical drugs, including Citrus × Aurantium L [Rutaceae; Aurantii Fructus Immaturus], Atractylodes Macrocephala Koidz. [Compositae; Rhizoma Atractylodis Macrocephalae], Bupleurum Chinense DC [Apiaceae; Radix Bupleuri Chinensis], and Crataegus Pinnatifida Bunge [Rosaceae; Fructus Crataegi Pinnatifidae], which have been widely used in clinical therapy for functional dyspepsia (FD). Aim of the study: This study aimed to evaluate the pharmacological effects and mechanisms of action of ZZKZ on gastric hypersensitivity and motor dysfunction in a rat model of FD. Materials and methods: FD was induced in Sprague-Dawley rats by neonatal gastric irritation with 0.1% iodoacetamide. The FD rats were treated with ZZKZ (0.5 g/kg, 1.0 g/kg, or 1.5 g/kg respectively) by gavage for 7 days, while domperidone (3 mg/kg) acted as treatment control. Body weight gain, food intake, gastric emptying, and intestinal propulsion were also measured. Ex vivo gastric smooth muscle activity recordings and greater splanchnic afferent (GSN) firing recordings were employed to evaluate gastric motility and sensation. Particularly, the role of 5-HT in the action of ZZKZ in improving gastric dysmotility and hypersensitivity was explored. Results: ZZKZ promoted weight gain, food intake, gastric emptying, and intestinal propulsion in FD rats. ZZKZ promoted spontaneous and ACh-induced contractions of gastric smooth muscle strips in FD rats, alleviated spontaneous activity, and chemical (acid perfusion) and mechanical (intragastric distension) stimulated GSN firing in FD rats. ZZKZ ameliorated gastric smooth muscle contraction and GSN firing induced by 5-HT in FD rats. ZZKZ stimulated the release of serum 5-HT, with reduced 5-HT3 receptor and increased 5-HT4 receptor mRNA expression in the guts of FD rats. Conclusion: This study demonstrated that ZZKZ improves FD-related gastric hypersensitivity and motor dysfunction and should be an effective compound for relieving FD symptoms. The gastric 5-HT system with lower 5-HT3 activity and increased 5-HT4 distribution is involved in the mechanisms of ZZKZ underlying the treatment of FD.

The BRD4 Inhibitor dBET57 Exerts Anticancer Effects by Targeting Superenhancer-Related Genes in Neuroblastoma.

Neuroblastoma (NB) is the most common solid tumor of the neural crest cell origin in children and has a poor prognosis in high-risk patients. The oncogene MYCN was found to be amplified at extremely high levels in approximately 20% of neuroblastoma cases. In recent years, research on the targeted hydrolysis of BRD4 to indirectly inhibit the transcription of the MYCN created by proteolysis targeting chimaera (PROTAC) technology has become very popular. dBET57 (S0137, Selleck, TX, USA) is a novel and potent heterobifunctional small molecule degrader based on PROTAC technology. The purpose of this study was to investigate the therapeutic effect of dBET57 in NB and its potential mechanism. In this study, we found that dBET57 can target BRD4 ubiquitination and disrupt the proliferation ability of NB cells. At the same time, dBET57 can also induce apoptosis, cell cycle arrest, and decrease migration. Furthermore, dBET57 also has a strong antiproliferation function in xenograft tumor models in vivo. In terms of mechanism, dBET57 targets the BET protein family and the MYCN protein family by associating with CRBN and destroys the SE landscape of NB cells. Combined with RNA-seq and ChIP-seq public database analysis, we identified the superenhancer-related genes TBX3 and ZMYND8 in NB as potential downstream targets of dBET57 and experimentally verified that they play an important role in the occurrence and development of NB. In conclusion, these results suggest that dBET57 may be an effective new therapeutic drug for the treatment of NB.