Beyond the base pairs: comparative genome-wide DNA methylation profiling across sequencing technologies.

Deoxyribonucleic acid (DNA) methylation plays a key role in gene regulation and is critical for development and human disease. Techniques such as whole-genome bisulfite sequencing (WGBS) and reduced representation bisulfite sequencing (RRBS) allow DNA methylation analysis at the genome scale, with Illumina NovaSeq 6000 and MGI Tech DNBSEQ-T7 being popular due to their efficiency and affordability. However, detailed comparative studies of their performance are not available. In this study, we constructed 60 WGBS and RRBS libraries for two platforms using different types of clinical samples and generated approximately 2.8 terabases of sequencing data. We systematically compared quality control metrics, genomic coverage, CpG methylation levels, intra- and interplatform correlations, and performance in detecting differentially methylated positions. Our results revealed that the DNBSEQ platform exhibited better raw read quality, although base quality recalibration indicated potential overestimation of base quality. The DNBSEQ platform also showed lower sequencing depth and less coverage uniformity in GC-rich regions than did the NovaSeq platform and tended to enrich methylated regions. Overall, both platforms demonstrated robust intra- and interplatform reproducibility for RRBS and WGBS, with NovaSeq performing better for WGBS, highlighting the importance of considering these factors when selecting a platform for bisulfite sequencing.

A novel subtype classification and corresponding surgical strategies for spinal dural cysts -a report of 104 cases.

BACKGROUND: The nomenclature, classification, and surgical approaches for spinal dural cysts (SDCs) remain a subject of controversy. PURPOSE: The present study proposes a novel subtype classification system and corresponding surgical strategies, with the aim of enhancing comprehension of this entity and standardizing surgical treatment. STUDY DESIGN: A retrospective review. PATIENT SAMPLE: A total of 104 patients with SDCs underwent novel subtype classification and corresponding surgical strategies from January 2015 to December 2021. Fifty-four patients who underwent conventional surgery from January 2012 to December 2014 as the control group for preliminary validation. OUTCOME MEASURES: The outcomes are categorized into 4 levels: excellent, good, unchanged, and deteriorated, based on neurological improvement and pain relief. Grades of excellent and good were identified as improvements. Follow-up magnetic resonance imaging and complications were also evaluated. METHODS: Based on the shared pathogenic factor of dural defects, the dural-associated cysts in the spinal canal are uniformly referred to as SDCs. They are further classified into Type 1 (no nerve roots) and Type 2 (containing nerve roots), with 4 additional subtypes based on the shape of the leak and the flow of leakage. The fissure-shaped leak of Type 1a SDCs is directly sutured, whereas the aperture-shaped leak of Type 1b is repaired using a patch. Low-flow leakage of Type 2a is directly sealed using a combination of adipose tissue and fibrin glue, whereas high-flow Type 2b necessitates suturing at the end of the leak to attenuate cerebrospinal fluid flow prior to sealing. RESULTS: The follow-up period averaged 23.8 months. Excellent or good outcomes were achieved in 100%, 88.9%, 100%, and 97.3% for the 4 subtypes respectively. The overall improvement rate of SDCs was 97.1%, which was significantly higher than that of the conventional surgery group (85.2%, p=.008). MRI follow-up showed a significant reduction in cyst size of 100%, 100%, 97.8%, and 97.3% for the 4 subtypes, respectively. The primary complications included pseudomeningocele in 4 cases (3.8%) and delayed wound healing in 5 cases (4.8%). The complication rate was also significantly lower than that of the control group (8.7% vs 24.1%, p=.008). CONCLUSIONS: Subtyping SDCs based on the variation of leaks and leakage can enable more targeted surgical strategies, which are helpful for improving treatment effectiveness and reducing complications.

The E3 ubiquitin ligase Herc1 modulates the response to nucleoside analogs in acute myeloid leukemia.

For several decades, induction therapy with nucleoside analogs, in particular cytarabine (Ara-C) and, to a lesser extent, fludarabine, has been the standard of care for patients diagnosed with acute myeloid leukemia (AML). Still, the anti-tumor efficacy of nucleoside analogs is often limited by intrinsic and acquired drug resistance, thereby leading to poor therapeutic response and suboptimal clinical outcomes. Here, we used genome-wide CRISPR-based pharmacogenomic screening to map the genetic factors that modulate the response to nucleoside analogs in AML and identified the E3 ubiquitin ligase Herc1 as a key modulator of Ara-C response in the MLL/AF9 (MA) and the HOXA9/MEIS1 (HM) murine AML models both in vitro and in vivo. Loss of HERC1 enhanced nucleoside analog-induced cell death in both murine and human AML cell lines by compromising cell cycle progression. In-depth proteomic analysis and subsequent validation identified deoxycytidine kinase Dck as a novel target of Herc1 in MA and HM murine cells. We observed that HERC1 is overexpressed in AML compared to other cancer types and higher HERC1 expression is associated with shorter overall survival of patients with AML in the TCGA and BEAT-AML cohorts. Collectively, this study highlights the importance of HERC1 in the response of AML cells to nucleoside analogs, thereby establishing this E3 ubiquitin ligase as a novel predictive biomarker and potential therapeutic target for the treatment of AML.

Discovery of novel coumarin-based KRAS-G12C inhibitors from virtual screening and Rational structural optimization.

KRAS-G12C inhibitors has been made significant progress in the treatment of KRAS-G12C mutant cancers, but their clinical application is limited due to the adaptive resistance, motivating development of novel structural inhibitors. Herein, series of coumarin derivatives as KRAS-G12C inhibitors were found through virtual screening and rational structural optimization. Especially, K45 exhibited strong antiproliferative potency on NCI-H23 and NCI-H358 cancer cells harboring KRAS-G12C with the IC50 values of 0.77 µM and 1.50 µM, which was 15 and 11 times as potent as positive drug ARS1620, respectively. Furthermore, K45 reduced the phosphorylation of KRAS downstream effectors ERK and AKT by reducing the active form of KRAS (KRAS GTP) in NCI-H23 cells. In addition, K45 induced cell apoptosis by increasing the expression of anti-apoptotic protein BAD and BAX in NCI-H23 cells. Docking studies displayed that the 3-naphthylmethoxy moiety of K45 extended into the cryptic pocket formed by the residues Gln99 and Val9, which enhanced the interaction with the KRAS-G12C protein. These results indicated that K45 was a potent KRAS-G12C inhibitor worthy of further study.

Clot removAl with or without decompRessive craniectomy under ICP monitoring for supratentorial IntraCerebral Hemorrhage (CARICH): a randomized controlled trial.

BACKGROUND: Decompressive craniectomy (DC), a surgery to remove part of the skull and open the dura mater, maybe an effective treatment for controlling intracranial hypertension. It remains great interest to elucidate whether DC is beneficial to intracerebral hemorrhage (ICH) patients who warrant clot removal (CR) to prevent intracranial hypertension. METHODS: The trial was a prospective, pragmatic, controlled trial involving adult patients with ICH who were undergoing removal of hematoma. ICH patients were randomly assigned at a 1:1 ratioto undergo CR with or without DC under the monitoring of intracranial pressure. The primary outcome was the proportion of unfavorable functional outcome (modified Rankin Scale 3-6) at 3 months. Secondary outcomes included the mortality at 3 months and the occurrence of reoperation. RESULTS: A total of 102 patients were assigned to the CR with DC group and 102 to the CR group. Median hematoma volume was 54.0 ml (range 30-80 ml) and median preoperative Glasgow Coma Scale was 10 (range 5-15). At 3 months, 94 patients (92.2%) in CR with DC group and 83 patients (81.4%) in the CR group had unfavorable functional outcome ( P =0.023). Fourteen patients (13.7%) in the CR with DC group died versus five patients (4.9%) in the CR group ( P =0.030). The number of patients with reoperation was similar between the CR with DC group and CR group (5.9 vs. 3.9%; P =0.517). Postoperative intracranial pressure values were not significantly different between two groups and the mean values were less than 20 mmHg. CONCLUSIONS: CR without DC decreased the rate of modified Rankin Scale score of 3-6 and mortality in patients with ICH, compared with CR with DC.

Robust Cooperative Fault-Tolerant Control for Uncertain Multi-Agent Systems Subject to Actuator Faults.

This article investigates the robust cooperative fault-tolerant control problem of multi-agent systems subject to mismatched uncertainties and actuator faults. During the design process of the intermediate variable estimator, there is no need to satisfy fault estimation matching conditions, and this overcomes a crucial constraint of traditional observers and estimators. The feedback term of the designed estimator contains the centralized estimation errors and the distributed estimation errors of the agent, and this further improves the design freedom of the proposed estimator. A novel fault-tolerant control protocol is designed based on the fault estimation information. In this work, the bounds of the fault and its derivatives are unknown, and the considered method is applicable to both directed and undirected multi-agent systems. Furthermore, the parameters of the estimator are determined through the resolution of a linear matrix inequality (LMI), which is decoupled by employing coordinate transformation and Schur decomposition. Lastly, a numerical simulation result is used to demonstrate the effectiveness of the proposed method.

Priority index for critical Covid-19 identifies clinically actionable targets and drugs.

While genome-wide studies have identified genomic loci in hosts associated with life-threatening Covid-19 (critical Covid-19), the challenge of resolving these loci hinders further identification of clinically actionable targets and drugs. Building upon our previous success, we here present a priority index solution designed to address this challenge, generating the target and drug resource that consists of two indexes: the target index and the drug index. The primary purpose of the target index is to identify clinically actionable targets by prioritising genes associated with Covid-19. We illustrate the validity of the target index by demonstrating its ability to identify pre-existing Covid-19 phase-III drug targets, with the majority of these targets being found at the leading prioritisation (leading targets). These leading targets have their evolutionary origins in Amniota ('four-leg vertebrates') and are predominantly involved in cytokine-cytokine receptor interactions and JAK-STAT signaling. The drug index highlights opportunities for repurposing clinically approved JAK-STAT inhibitors, either individually or in combination. This proposed strategic focus on the JAK-STAT pathway is supported by the active pursuit of therapeutic agents targeting this pathway in ongoing phase-II/III clinical trials for Covid-19.

mHapBrowser: a comprehensive database for visualization and analysis of DNA methylation haplotypes.

DNA methylation acts as a vital epigenetic regulatory mechanism involved in controlling gene expression. Advances in sequencing technologies have enabled characterization of methylation patterns at single-base resolution using bisulfite sequencing approaches. However, existing methylation databases have primarily focused on mean methylation levels, overlooking phased methylation patterns. The methylation status of CpGs on individual sequencing reads represents discrete DNA methylation haplotypes (mHaps). Here, we present mHapBrowser, a comprehensive database for visualizing and analyzing mHaps. We systematically processed data of diverse tissues in human, mouse and rat from public repositories, generating mHap format files for 6366 samples. mHapBrowser enables users to visualize eight mHap metrics across the genome through an integrated WashU Epigenome Browser. It also provides an online server for comparing mHap patterns across samples. Additionally, mHap files for all samples can be downloaded to facilitate local processing using downstream analysis toolkits. The utilities of mHapBrowser were demonstrated through three case studies: (i) mHap patterns are associated with gene expression; (ii) changes in mHap patterns independent of mean methylation correlate with differential expression between lung cancer subtypes; and (iii) the mHap metric MHL outperforms mean methylation for classifying tumor and normal samples from cell-free DNA. The database is freely accessible at http://mhap.sibcb.ac.cn/.

Distributed Robust Fault Estimation for Multiagent Systems Based on Transition Variable Estimator.

This article investigates the distributed robust fault estimation for a class of multiagent systems with actuator faults and nonlinear uncertainties. To estimate the actuator faults and system states simultaneously, a novel transition variable estimator is constructed. Compared with existing similar results, the fault estimator existing condition is not necessary for designing the transition variable estimator. Furthermore, the bounds of the faults and their derivatives can be unknown in designing the estimator for each agent in the system. The parameters of the estimator are calculated by using Schur decomposition and linear matrix inequality algorithm. Finally, the performance of the proposed method is demonstrated through experiments of wheeled mobile robots.

A DNA methylation haplotype block landscape in human tissues and preimplantation embryos reveals regulatory elements defined by comethylation patterns.

DNA methylation and associated regulatory elements play a crucial role in gene expression regulation. Previous studies have focused primarily on the distribution of mean methylation levels. Advances in whole-genome bisulfite sequencing (WGBS) have enabled the characterization of DNA methylation haplotypes (MHAPs), representing CpG sites from the same read fragment on a single chromosome, and the subsequent identification of methylation haplotype blocks (MHBs), in which adjacent CpGs on the same fragment are comethylated. Using our expert-curated WGBS data sets, we report comprehensive landscapes of MHBs in 17 representative normal somatic human tissues and during early human embryonic development. Integrative analysis reveals MHBs as a distinctive type of regulatory element characterized by comethylation patterns rather than mean methylation levels. We show the enrichment of MHBs in open chromatin regions, tissue-specific histone marks, and enhancers, including super-enhancers. Moreover, we find that MHBs tend to localize near tissue-specific genes and show an association with differential gene expression that is independent of mean methylation. Similar findings are observed in the context of human embryonic development, highlighting the dynamic nature of MHBs during early development. Collectively, our comprehensive MHB landscapes provide valuable insights into the tissue specificity and developmental dynamics of DNA methylation.

DNA methylation profiling to determine the primary sites of metastatic cancers using formalin-fixed paraffin-embedded tissues.

Identifying the primary site of metastatic cancer is critical to guiding the subsequent treatment. Approximately 3-9% of metastatic patients are diagnosed with cancer of unknown primary sites (CUP) even after a comprehensive diagnostic workup. However, a widely accepted molecular test is still not available. Here, we report a method that applies formalin-fixed, paraffin-embedded tissues to construct reduced representation bisulfite sequencing libraries (FFPE-RRBS). We then generate and systematically evaluate 28 molecular classifiers, built on four DNA methylation scoring methods and seven machine learning approaches, using the RRBS library dataset of 498 fresh-frozen tumor tissues from primary cancer patients. Among these classifiers, the beta value-based linear support vector (BELIVE) performs the best, achieving overall accuracies of 81-93% for identifying the primary sites in 215 metastatic patients using top-k predictions (k = 1, 2, 3). Coincidentally, BELIVE also successfully predicts the tissue of origin in 81-93% of CUP patients (n = 68).

TRAmHap: accurate prediction of transcriptional activity from DNA methylation haplotypes in bisulfite-sequencing data.

Deoxyribonucleic acid (DNA) methylation (DNAm) is an important epigenetic mechanism that plays a role in chromatin structure and transcriptional regulation. Elucidating the relationship between DNAm and gene expression is of great importance for understanding its role in transcriptional regulation. The conventional approach is to construct machine-learning-based methods to predict gene expression based on mean methylation signals in promoter regions. However, this type of strategy only explains about 25% of gene expression variation, and hence is inadequate in elucidating the relationship between DNAm and transcriptional activity. In addition, using mean methylation as input features neglects the heterogeneity of cell populations that can be reflected by DNAm haplotypes. We here developed TRAmaHap, a novel deep-learning framework that predicts gene expression by utilizing the characteristics of DNAm haplotypes in proximal promoters and distal enhancers. Using benchmark data of human and mouse normal tissues, TRAmHap shows much higher accuracy than existing machine-learning based methods, by explaining 60~80% of gene expression variation across tissue types and disease conditions. Our model demonstrated that gene expression can be accurately predicted by DNAm patterns in promoters and long-range enhancers as far as 25 kb away from transcription start site, especially in the presence of intra-gene chromatin interactions.

Swc4 protects nucleosome-free rDNA, tDNA and telomere loci to inhibit genome instability.

In the baker's yeast Saccharomyces cerevisiae, NuA4 and SWR1-C, two multisubunit complexes, are involved in histone acetylation and chromatin remodeling, respectively. Eaf1 is the assembly platform subunit of NuA4, Swr1 is the assembly platform and catalytic subunit of SWR1-C, while Swc4, Yaf9, Arp4 and Act1 form a functional module, and is present in both NuA4 and SWR1 complexes. ACT1 and ARP4 are essential for cell survival. Deletion of SWC4, but not YAF9, EAF1 or SWR1 results in a severe growth defect, but the underlying mechanism remains largely unknown. Here, we show that swc4Δ, but not yaf9Δ, eaf1Δ, or swr1Δ cells display defects in DNA ploidy and chromosome segregation, suggesting that the defects observed in swc4Δ cells are independent of NuA4 or SWR1-C integrity. Swc4 is enriched in the nucleosome-free regions (NFRs) of the genome, including characteristic regions of RDN5s, tDNAs and telomeres, independently of Yaf9, Eaf1 or Swr1. In particular, rDNA, tDNA and telomere loci are more unstable and prone to recombination in the swc4Δ cells than in wild-type cells. Taken together, we conclude that the chromatin associated Swc4 protects nucleosome-free chromatin of rDNA, tDNA and telomere loci to ensure genome integrity.

Ursolic acid ameliorates traumatic brain injury in mice by regulating microRNA-141-mediated PDCD4/PI3K/AKT signaling pathway.

BACKGROUND: Neuronal apoptosis and inflammation are the key pathogenic features of secondary brain injury, which results in the neurological impairment that traumatic brain injury (TBI) patients experience. Ursolic Acid (UA) has been shown to have neuroprotective properties against brain damage, however, detailed mechanisms have not been fully disclosed. Research on brain-related microRNAs (miRNAs) has opened up new possibilities for the neuroprotective treatment of UA by manipulating miRNAs. The present study was designed to investigate the impact of UA on neuronal apoptosis and the inflammatory response in TBI mice. METHODS: The mice's neurologic condition was assessed using the modified neurological severity score (mNSS) and the learning and memory abilities were assessed using the Morris water maze (MWM). Cell apoptosis, oxidative stress, and inflammation were utilized to examine the impact of UA on neuronal pathological damage. miR-141-3p was selected to evaluate whether UA influences miRNAs in a way that has neuroprotective benefits. RESULTS: The results showed that UA markedly decreased brain edema and neuronal mortality through oxidative stress and neuroinflammation in TBI mice. Using data from the GEO database, we found that miR-141-3p was considerably downregulated in TBI mice and that this downregulation was reversed by UA treatment. Further studies have shown that UA regulates miR-141-3p expression to exhibit its neuroprotective effect in mouse models and cell injury models. Then, miR-141-3p was discovered to directly target PDCD4 in TBI mice and neurons, a well-known PI3K/AKT pathway regulator in the neurons. Most importantly, the upregulation of phosphorylated (p)-AKT and p-PI3K provided the most compelling evidence that UA reactivated the PI3K/AKT pathway in the TBI mouse model, which was through regulating miR-141-3p. CONCLUSION: Our findings support the notion that UA can improve TBI by modulating miR-141 mediated PDCD4/PI3K/AKT signaling pathway.

1H-Indazoles derivatives targeting PI3K/AKT/mTOR pathway: Synthesis, anti-tumor effect and molecular mechanism.

The PI3K/AKT/mTOR signaling pathway is one of the most common abnormal activation pathways in tumor cells, and has associated with multiple functions such as tumor cell growth, proliferation, migration, invasion, and tumor angiogenesis. Here, a series of 3-amino-1H-indazole derivatives were synthesized, and their antiproliferative activities against HT-29, MCF-7, A-549, HepG2 and HGC-27 cells were evaluated. Among them, W24 exhibited the broad-spectrum antiproliferative activity against four cancer cells with IC50 values of 0.43-3.88 µM. Mechanism studies revealed that W24 inhibited proliferation by affecting the DNA synthesis, induced G2/M cell cycle arrest and apoptosis by regulating Cyclin B1, BAD and Bcl-xL, meanwhile induced the change of intracellular ROS and mitochondrial membrane potential in HGC-27 cells. Moreover, W24 inhibited the migration and invasion of HGC-27 cells by decreasing EMT pathway related proteins and reducing the mRNA expression levels of Snail, Slug and HIF-1α. Furthermore, W24 displayed low tissue toxicity profile and good pharmacokinetic properties in vivo. Therefore, 3-amino-1H-indazole derivatives might serve as a new scaffold for the development of PI3K/AKT/mTOR inhibitor and anti-gastric cancer reagent.

Amelioration of White Matter Injury Through Mitigating Ferroptosis Following Hepcidin Treatment After Spinal Cord Injury.

Spinal cord injury (SCI) usually introduces permanent or long-lasting neurological impairments. Maintaining the integrity of the limited number of white matter bundles (5-10%) preserves wholly or partially locomotor following SCI. Considering that the basic structure of white matter bundles is axon wrapped by oligodendrocytes, promoting oligodendrocytes survival might be a feasible strategy for reducing white matter injury (WMI) after SCI. Oligodendrocytes are rich in unsaturated fatty acid and susceptible to ferroptosis-induced damage. Hence, exploring method to reduce ferroptosis is supposed to expedite oligodendrocytes survival, thereafter mitigating WMI to facilitate functional recovery post-SCI. Here, the results indicated the administration of hepcidin reduced iron accumulation to promote oligodendrocytes survival and to decrease spinal cord atrophy, therefore facilitating functional recovery. Then, the WMI was evidently decreased owing to attenuating ferroptosis. Subsequently, the results revealed that the expression of divalent metal transporter 1 (DMT1) and transferrin receptor (TfR) was expressed in CC1+ cells. The expression level of DMT1 and TfR was significantly increased, while this phenomenon was obviously neutralized with the administration of hepcidin in the epicenter of spinal cord after SCI. Afterward, the application of hepcidin downregulated reactive oxygen species (ROS) overload, which was evidently increased with the treatment of 20 µM FeCl3, therefore increasing cell viability and reducing lactate dehydrogenase (LDH) activity through downregulating the expression of DMT1 and TfR to inhibit ferroptosis in oligodendrocyte progenitor cells (OPCs). The present study provides evidence that the application of hepcidin facilitates oligodendrocytes survival to alleviate WMI via reducing the expression of DMT1 and TfR.

Chromosome territory reorganization through artificial chromosome fusion is compatible with cell fate determination and mouse development.

Chromosomes occupy discrete spaces in the interphase cell nucleus, called chromosome territory. The structural and functional relevance of chromosome territory remains elusive. We fused chromosome 15 and 17 in mouse haploid embryonic stem cells (haESCs), resulting in distinct changes of territories in the cognate chromosomes, but with little effect on gene expression, pluripotency and gamete functions of haESCs. The karyotype-engineered haESCs were successfully implemented in generating heterozygous (2n = 39) and homozygous (2n = 38) mouse models. Mice containing the fusion chromosome are fertile, and their representative tissues and organs display no phenotypic abnormalities, suggesting unscathed development. These results indicate that the mammalian chromosome architectures are highly resilient, and reorganization of chromosome territories can be readily tolerated during cell differentiation and mouse development.

Design, synthesis, and biological evaluation of quinoxalinone derivatives as potent BRD4 inhibitors.

The bromodomain-containing protein 4 (BRD4) has gained growing interest as an effective drug target for the treatment of hepatocellular carcinoma (HCC). Herein, we designed and synthesized a series of quinoxalinone derivatives as BRD4 inhibitors via scaffold hopping. The representative compound X9 showed potent BRD4 inhibitory activity (with IC50 = 82.3 nM), and preferable antiproliferative activity against HepG2 cells (with IC50 = 1.13 ± 0.07 µM), as well as less toxicity against GES-1 cells (with IC50 = 57.24 ± 5.46 µM). Furthermore, compound X9 dose-dependently inhibited colony formation and blocked the migration of HepG2 cells by down-regulating the expression of Snail and MMP-9 while up-regulating the E-cadherin and Occludin. Besides, compound X9 efficiently down-regulated the expression of c-Myc in HepG2 cells, induced apoptosis, and arrested at G0/G1 phase. In total, quinoxalinone was a potential core as BRD4 inhibitor and compound X9 might be effective for liver cancer therapy.

Neural network-based event-triggered data-driven control of disturbed nonlinear systems with quantized input.

This paper is devoted to design an event-triggered data-driven control for a class of disturbed nonlinear systems with quantized input. A uniform quantizer reconstructed with decreasing quantization intervals is employed to reduce the quantization error. A neural network-based estimation strategy is proposed to estimate both the pseudo partial derivative and disturbances. Consequently, an input triggering rule for single-input single-output systems is provided by incorporating the estimated disturbances, the quantization error bound and tracking errors. Resorting to the Lyapunov method, sufficient conditions for synthesized error systems to be uniformly ultimately bounded are presented. The validity of the proposed scheme is demonstrated via a simulation example.

Discovery of novel VEGFR-2-PROTAC degraders based on the localization of lysine residues via recruiting VHL for the treatment of gastric cancer.

VEGFR-2 is an attractive therapeutic target for antitumor drug research by blocking tumor angiogenesis and PROTAC provides a new technology for targeted protein knockout. Herein, a library of novel VEGFR-2-PROTAC degraders were rationally designed and synthesized based on the Lys residue region on the surface of VEGFR-2 protein using protein structure-based drug design strategy. Among them, P7 exhibited preferable antitumor activity against HGC-27 cells and less toxic to human normal HUVEC, HEK293T and GES-1 cells in vitro, as well as the potent degradation activity of VEGFR-2 protein in HGC-27 cells (DC50: 0.084 ± 0.04 µM, Dmax: 73.7%) and HUVEC cells (DC50: 0.51 ± 0.10 µM, Dmax: 76.6%). Additionally, P7 degraded VEGFR-2 protein by the formation of ternary complex and the ubiquitin proteasome pathway in HGC-27 cells. Furthermore, P7 shortened the half-life of VEGFR-2 protein synthesis and had no inhibitory effect on the expression of VEGFR-2 mRNA in HGC-27 cells. Moreover, P7 inhibited the colony formation, migration and invasion of HGC-27 cells in a time- and dose-dependent manner, and meanwhile induced G2/M phase cycle arrest and apoptosis. All the results demonstrated that P7 could be as a promising VEGFR-2-PROTAC degrader for gastric cancer therapy.