Conformational studies of biaryl-bridged seven-membered lactones with a quaternary carbon center.

We show the synthesis and conformational studies of a series of 7,7-disubstituted-dibenzo[b,d]oxepin-6(7H)-ones that feature biaryl-bridged seven-membered lactones with a quaternary carbon center, in which the larger substituents prefer the axial positions. Further studies on the crystal structures and DFT calculations revealed that the high selectivity observed is attributed to the volume of substituents.

DEAD-box RNA helicase RH20 positively regulates RNAi-based antiviral immunity in plants by associating with SGS3/RDR6 bodies.

RNA silencing plays a crucial role in defending against viral infections in diverse eukaryotic hosts. Despite extensive studies on core components of the antiviral RNAi pathway such as DCLs, AGOs and RDRs proteins, host factors involved in antiviral RNAi remain incompletely understood. In this study, we employed the proximity labelling approach to identify the host factors required for antiviral RNAi in Nicotiana benthamiana. Using the barley stripe mosaic virus (BSMV)-encoded γb, a viral suppressor of RNA silencing (VSR), as the bait protein, we identified the DEAD-box RNA helicase RH20, a broadly conserved protein in plants and animals with a homologous human protein known as DDX5. We demonstrated the interaction between RH20 and BSMV γb. Knockdown or knockout of RH20 attenuates the accumulation of viral small interfering RNAs, leading to increased susceptibility to BSMV, while overexpression of RH20 enhances resistance to BSMV, a process requiring the cytoplasmic localization and RNA-binding activity of RH20. In addition to BSMV, RH20 also negatively regulates the infection of several other positive-sense RNA viruses, suggesting the broad-spectrum antiviral activity of RH20. Mechanistic analysis revealed the colocalization and interaction of RH20 with SGS3/RDR6, and disruption of either SGS3 or RDR6 undermines the antiviral function of RH20, suggesting RH20 as a new component of the SGS3/RDR6 bodies. As a counter-defence, BSMV γb VSR subverts the RH20-mediated antiviral defence by interfering with the RH20-SGS3 interaction. Our results uncover RH20 as a new positive regulator of antiviral RNAi and provide new potential targets for controlling plant viral diseases.

Membrane-mediated modulation of mitochondrial physiology by terahertz waves.

Extensive studies have demonstrated the diverse impacts of electromagnetic waves at gigahertz and terahertz (THz) frequencies on cytoplasmic membrane properties. However, there is little evidence of these impacts on intracellular membranes, particularly mitochondrial membranes crucial for mitochondrial physiology. In this study, human neuroblast-like cells were exposed to continuous 0.1 THz radiation at an average power density of 33 mW/cm2. The analysis revealed that THz exposure significantly altered the mitochondrial ultrastructure. THz waves enhanced the enzymatic activity of the mitochondrial respiratory chain but disrupted supercomplex assembly, compromising mitochondrial respiration. Molecular dynamics simulations revealed altered rates of change in the quantity of hydrogen bonds and infiltration of water molecules in lipid bilayers containing cardiolipin, indicating the specific behavior of cardiolipin, a signature phospholipid in mitochondria, under THz exposure. These findings suggest that THz radiation can significantly alter mitochondrial membrane properties, impacting mitochondrial physiology through a mechanism related to mitochondrial membrane, and provide deeper insight into the bioeffects of THz radiation.

Advancements and trends in exosome research in lung cancer from a bibliometric analysis (2004-2023).

Background: Lung cancer, characterized by its high morbidity and lethality, necessitates thorough research to enhance our understanding of its pathogenesis and discover novel therapeutic approaches. Recent studies increasingly demonstrate that lung cancer cells can modulate the tumor microenvironment, promoting tumor growth, and metastasis through the release of exosomes. Exosomes are small vesicles secreted by cells and contain a variety of bioactive molecules such as proteins, nucleic acids, and metabolites. This paper presents a comprehensive review of exosome research in lung cancer and its progress through bibliometric analysis. Methods: Publications related to exosomes in lung cancer patients were systematically searched on the Web of Science Core Collection (WoSCC) database. Bibliometric analysis was performed using VOSviwers, CiteSpace, and the R package "Bibliometrics". Publications were quantitatively analyzed using Microsoft Office Excel 2019. The language of publication was restricted to "English" and the search strategy employed TS=(exosomes or exosomes or exosomes) and TS=(lung cancer). The search period commenced on January 1, 2004, and concluded on November 12, 2023, at noon. The selected literature types included Articles and Reviews. Results: The study encompassed 1699 papers from 521 journals across 71 countries and 2105 institutions. Analysis revealed a consistent upward trend in lung cancer exosome research over the years, with a notable surge in recent times. This surge indicates a growing interest and depth of inquiry into lung cancer exosomes. Major research institutions in China and the United States, including Nanjing Medical University, Shanghai Jiao Tong University, Chinese Academy Of Sciences, and Utmd Anderson Cancer Center, emerged as crucial research hubs. The annual publication count in this field witnessed a continuous rise, particularly in recent years. Key terms such as lung cancer, non-small cell lung cancer (NSCLC), microvesicles, intercellular communication, exosomal miRNAs, and oncology dominated the research landscape. Fields like cell biology, biochemistry, biotechnology, and oncology exhibited close relation with this research. Clotilde Théry emerged as the most cited author in the field, underlining her significant contributions. These results demonstrate the broad impact of exosome research in lung cancer, with key terms covering not only disease-specific aspects such as lung cancer and NSCLC but also basic biological concepts like microvesicles and intercellular communication. Explorations into exosomal microRNAs and oncology have opened new avenues for lung cancer exosome research. In summary, lung cancer exosome research is poised to continue receiving attention, potentially leading to breakthroughs in treatment and prevention. Conclusion: Publications on lung cancer exosomes show a rising trend year by year, with China and the United States ranking first and second in terms of the number of publications. However, there is insufficient academic learning cooperation and exchanges between the two sides, and Chinese universities account for a large proportion of research institutions in this field. Jing Li is the most productive author, Clotilde Théry is the most co-cited author, and Cancers is the journal with the highest number of publications. The current focus in the field of lung cancer exosomes is on biomarkers, liquid biopsies, immunotherapy, and tumor microenvironment.

Flavin-containing monooxygenases FMOGS-OXs integrate flowering transition and salt tolerance in Arabidopsis thaliana.

Salt stress substantially leads to flowering delay. The regulation of salt-induced late flowering has been studied at the transcriptional and protein levels; however, the involvement of secondary metabolites has rarely been investigated. Here, we report that FMOGS-OXs (EC 1.14.13.237), the enzymes that catalyze the biosynthesis of glucosinolates (GSLs), promote flowering transition in Arabidopsis thaliana. It has been reported that WRKY75 is a positive regulator, and MAF4 is a negative regulator of flowering transition. The products of FMOGS-OXs, methylsulfinylalkyl GSLs (MS GSLs), facilitate flowering by inducing WRKY75 and repressing the MAS-MAF4 module. We further show that the degradation of MS GSLs is involved in salt-induced late flowering and salt tolerance. Salt stress induces the expression of myrosinase genes, resulting in the degradation of MS GSLs, thereby relieving the promotion of WRKY75 and inhibition of MAF4, leading to delayed flowering. In addition, the degradation products derived from MS GSLs enhance salt tolerance. Previous studies have revealed that FMOGS-OXs exhibit alternative catalytic activity to form trimethylamine N-oxide (TMAO) under salt stress, which activates multiple stress-related genes to promote salt tolerance. Therefore, FMOGS-OXs integrate flowering transition and salt tolerance in various ways. Our study shed light on the functional diversity of GSLs and established a connection between flowering transition, salt resistance, and GSL metabolism.

SERS detection of volatile gas in spoiled pork with the Ag/MoS2 nano-flower cavity/PVDF micron-bowl cavity (FIB) substrate.

Putrescine and cadaverine are significant volatile indicators used to assess the degree of food spoilage. Herein, we propose a micro-nano multi cavity structure for surface-enhanced Raman spectroscopy (SERS) to analyze the volatile gas putrescine and cadaverine in decomposing food. The MoS2 nano-flowers are inserted into a PVDF micro-cavity through in-situ growth, followed by vacuum evaporation technology of Ag nanoparticles to form an Ag/MoS2 nano-flower cavity/PVDF micron-bowl cavity (FIB) substrate. The micro-nano multi cavity structure can improve the capture capacity of both light and gas, thereby exhibiting high sensitivity (EF = 7.71 × 107) and excellent capability for gas detection of 2-naphthalenethiol. The SERS detections of the putrescine and cadaverine are achieved in the spoiled pork samples with the FIB substrate. Therefore, this substrate can provide an efficient, accurate, and feasible method for the specific and quantitative detection in the food safety field.

Structural Insights and Influence of Terahertz Waves in Midinfrared Region on Kv1.2 Channel Selectivity Filter.

Potassium ion channels are the structural basis for excitation transmission, heartbeat, and other biological processes. The selectivity filter is a critical structural component of potassium ion channels, whose structure is crucial to realizing their function. As biomolecules vibrate and rotate at frequencies in the terahertz band, potassium ion channels are sensitive to terahertz waves. Therefore, it is worthwhile to investigate how the terahertz wave influences the selectivity filter of the potassium channels. In this study, we investigate the structure of the selectivity filter of Kv1.2 potassium ion channels using molecular dynamics simulations. The effect of an electric field on the channel has been examined at four different resonant frequencies of the carbonyl group in SF: 36.75 37.06, 37.68, and 38.2 THz. As indicated by the results, 376GLY appears to be the critical residue in the selectivity filter of the Kv1.2 channel. Its dihedral angle torsion is detrimental to the channel structural stability and the transmembrane movement of potassium ions. 36.75 THz is the resonance frequency of the carbonyl group of 376GLY. Among all four frequencies explored, the applied terahertz electric field of this frequency has the most significant impact on the channel structure, negatively impacting the channel stability and reducing the ion permeability by 20.2% compared to the absence of fields. In this study, we simulate that terahertz waves in the mid-infrared frequency region can significantly alter the structure and function of potassium ion channels and that the effects of terahertz waves differ greatly based on frequency.

Application of Tryptophan and Methionine in Broccoli Seedlings Enhances Formation of Anticancer Compounds Sulforaphane and Indole-3-Carbinol and Promotes Growth.

Broccoli is a popular cruciferous vegetable that is well known for its abundant health-promoting biochemicals. The most important of these beneficial biochemicals are glucosinolates, including glucoraphanin and glucobrassicin. Glucoraphanin and glucobrassicin can be broken down by myrosinases into sulforaphane and indole-3-carbinol, which have been demonstrated to have potent cancer-preventive properties. Efforts to increase glucoraphanin in broccoli seedlings have long been a focus; however, increasing glucoraphanin and glucobrassicin simultaneously, as well as enhancing myrosinase activity to release more sulforaphane and indole-3-carbinol, have yet to be investigated. This study aims to investigate the impact of the combined application of tryptophan and methionine on the accumulation of sulforaphane and indole-3-carbinol, as well as their precursors. Furthermore, we also examined whether this application has any effects on seedling growth and the presence of other beneficial compounds. We found that the application of methionine and tryptophan not only increased the glucoraphanin content by 2.37 times and the glucobrassicin content by 3.01 times, but that it also caused a higher myrosinase activity, resulting in a1.99 times increase in sulforaphane and a 3.05 times increase in indole-3-carbinol. In addition, better plant growth and an increase in amino acids and flavonoids were observed in broccoli seedlings with this application. In conclusion, the simultaneous application of tryptophan and methionine to broccoli seedlings can effectively enhance their health-promoting value and growth. Our study provides a cost-effective and multi-benefit strategy for improving the health value and yield of broccoli seedlings, benefiting both consumers and farmers.

Cascade Bowl Multicavity Structure for In Situ Surface-Enhanced Raman Scattering Detection of Organic Gas Molecules.

With the increasing emphasis on atmospheric environmental protection, it is crucial to find an efficient, direct, and accurate method to identify pollutant species in the atmosphere. To solve this problem, we designed and prepared the cascade multicavity (CMC) structure composed with silver nanoparticles (Ag NPs) as a surface-enhanced Raman scattering (SERS) substrate with favorable light transmittance and flexibility. The multicavity structure distributed on the surface introducing the homogeneous connecting holes endows the structure to more fully utilize the incident light while slowing the gas movement rate. Theoretical and experimental results have demonstrated that the Ag NPs/cascade multicavity (Ag-CMC) SERS substrate is a highly sensitive SERS substrate that can be used for in situ detection of gases under non-perpendicularly incident laser irradiation or bending of the substrate. We believe that the SERS substrate can provide a more efficient and feasible way for in situ detection of gaseous pollutants.

Reversible Thermoelectric Regulation of Electromagnetic and Chemical Enhancement for Rapid SERS Detection.

Actively controlling surface-enhanced Raman scattering (SERS) performance plays a vital role in highly sensitive detection or in situ monitoring. Nevertheless, it is still challenging to achieve further modulation of electromagnetic enhancement and chemical enhancement simultaneously in SERS detection. In this study, a silver nanocavity structure with graphene as a spacer layer is coupled with thermoelectric semiconductor P-type gallium nitride (GaN) to form an electric-field-induced SERS (E-SERS) for dual enhancement. After applying the electric field, the intensity of SERS signals is further enhanced by over 10 times. The thermoelectric field enables fast and reproducible doping of graphene, thereby modulating its Fermi level over a wide range. The thermoelectric field also regulates the position of the plasmon resonance peak of the silver nanocavity structure, rendering synchronous dual electromagnetic and chemical regulation. Additionally, the method enables the trace detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A detailed theoretical analysis is performed based on the experimental results and finite-element calculations, paving the way for the fabrication of high-efficient E-SERS substrates.

Thermoelectrically Driven Dual-Mechanism Regulation on SERS and Application Potential for Rapid Detection of SARS-CoV-2 Viruses and Microplastics.

Electric-induced surface-enhanced Raman scattering (E-SERS) has been widely studied for its flexible regulation of SERS after the substrate is prepared. However, the enhancement effect is not sufficiently high in the E-SERS technology reported thus far, and no suitable field of application exists. In this study, a highly sensitive thermoelectrically induced SERS substrate, Ag/graphene/ZnO (AGZ), was fabricated using ZnO nanoarrays (NRs), graphene, and Ag nanoparticles (NPs). Applying a temperature gradient to the ZnO NRs enhanced the SERS signals of the probe molecules by a factor of approximately 20. Theoretical and experimental results showed that the thermoelectric potential enables the simultaneous modulation of the Fermi energy level of graphene and the plasma resonance peak of Ag NPs, resulting in a double enhancement in terms of physical and chemical mechanisms. The AGZ substrate was then combined with a mask to create a wearable thermoelectrically enhanced SERS mask for collecting SARS-CoV-2 viruses and microplastics. Its SERS signal can be enhanced by the temperature gradient created between a body heat source (∼37 °C) and a cold environment. The suitability of this method for virus detection was also examined using a reverse transcription-polymerase chain reaction and SARS-CoV-2 virus antigen detection. This work offers new horizons for research of E-SERS, and its application potential for rapid detection of the SARS-CoV-2 virus and microplastics was also studied.

Transcription factor PbNAC71 regulates xylem and vessel development to control plant height.

Dwarfism is an important agronomic trait in fruit breeding programs. However, the germplasm resources required to generate dwarf pear (Pyrus spp.) varieties are limited. Moreover, the mechanisms underlying dwarfism remain unclear. In this study, "Yunnan" quince (Cydonia oblonga Mill.) had a dwarfing effect on "Zaosu" pear. Additionally, the dwarfism-related NAC transcription factor gene PbNAC71 was isolated from pear trees comprising "Zaosu" (scion) grafted onto "Yunnan" quince (rootstock). Transgenic Nicotiana benthamiana and pear OHF-333 (Pyrus communis) plants overexpressing PbNAC71 exhibited dwarfism, with a substantially smaller xylem and vessel area relative to the wild-type controls. Yeast one-hybrid, dual-luciferase, chromatin immunoprecipitation-qPCR, and electrophoretic mobility shift assays indicated that PbNAC71 downregulates PbWalls are thin 1 expression by binding to NAC-binding elements in its promoter. Yeast two-hybrid assays showed that PbNAC71 interacts with the E3 ubiquitin ligase PbRING finger protein 217 (PbRNF217). Furthermore, PbRNF217 promotes the ubiquitin-mediated degradation of PbNAC71 by the 26S proteasome, thereby regulating plant height as well as xylem and vessel development. Our findings reveal a mechanism underlying pear dwarfism and expand our understanding of the molecular basis of dwarfism in woody plants.

Deciphering the pivotal role of people with high-frequency occupational animal exposure in antibiotic resistance transmission between humans and animals.

BACKGROUND: The spread of antibiotic-resistant bacteria (ARB) and antibiotic resistance genes (ARGs) among humans and food-producing animals has been widely reported. However, the transmission routes and associated risk factors remain incompletely understood. METHODS: Here, we used commensal Escherichia coli bacteria strains from faeces of pigs and local citizens [HEG: high exposure group (pig breeders, butchers or restaurant chefs) and LEG: low exposure group (other occupations)] to explore the dynamics of ARB and ARG transmission between animals and humans. RESULTS: Most ARGs (96%) present in pigs were shared with humans. Carriage rates of the shared ARGs suggest two transmission patterns among pigs, the HEG and LEG: one pattern was highest in pigs, gradually decreasing in the HEG and LEG (e.g. floR and cmlA1); the other pattern was increasing from pigs to the HEG but then decreasing in the LEG (e.g. mcr-1.1). Carriage rates of the HEG were higher than in the LEG in both patterns, implicating the HEG as a crucial medium in transmitting ARB and ARGs between food-producing animals and humans. Moreover, frequent inter/intragroup transmission via strains, plasmids and/or mobile elements was evident. Carriage of mcr-1.1 on human-gut-prevalent plasmids possibly promoted its enrichment in the HEG. CONCLUSIONS: The HEG is a crucial factor in transmitting ARB and ARGs between food-producing animals and humans. Rational measures to contain the risks of occupational exposure are urgently needed to keep dissemination of antibiotic resistance in check and safeguard public health.

metamedian: An R package for meta-analyzing studies reporting medians.

When performing an aggregate data meta-analysis of a continuous outcome, researchers often come across primary studies that report the sample median of the outcome. However, standard meta-analytic methods typically cannot be directly applied in this setting. In recent years, there has been substantial development in statistical methods to incorporate primary studies reporting sample medians in meta-analysis, yet there are currently no comprehensive software tools implementing these methods. In this paper, we present the metamedian R package, a freely available and open-source software tool for meta-analyzing primary studies that report sample medians. We summarize the main features of the software and illustrate its application through real data examples involving risk factors for a severe course of COVID-19.

Relationship between STAP1 methylation in peripheral blood T cells and the clinicopathological characteristics and prognosis of patients within 5-cm diameter HCC.

BACKGROUND: The aim of this study is to explore the methylation of signal transduction adaptor protein 1 (STAP1) in peripheral blood T cells as a prognostic marker for hepatocellular carcinoma (HCC) ≤5 cm. METHODS: A total of 66 HCC patients who visited our hospital from November 2012 to June 2016 were retrospectively analyzed, and 55 patients who met the inclusion and exclusion criteria were studied. Clinical and pathological data were collected from all patients to detect STAP1 methylation. STAP1 methylation expression was analyzed in HCC patients ≤5 cm with different clinicopathological features; univariate and independent prognostic factors were analyzed in HCC patients; and the relationship between STAP1 methylation expression and prognosis was analyzed in HCC patients. RESULTS: There was no significant difference in STAP1 methylation expression between patients with different gender, age, history of alcoholism, history of liver cirrhosis, recurrence, 3-year OS, 5-year OS, treatment, number of tumors, tumor diameter, HBV-DNA, HBSAg, Hbe-Ag expression, and AFP level (P>0.05); however, there was significant difference in STAP1 methylation expression between patients with different survival, 3-year DFS, and 5-year DFS (P<0.05). Multivariate Cox regression analysis showed that recurrence and STAP1 methylation were independent factors for OS and DFS (P<0.05). Kaplan-Meier survival curve results showed that the median survival time, OS, and DFS of STAP1 hypermethylation expression were shorter than those of hypomethylation (P<0.05). CONCLUSIONS: STAP1 methylation in peripheral blood T cells serves as a potential prognostic marker for HCC ≤5 cm.

Roadmap on multifunctional materials for drug delivery.

This Roadmap on drug delivery aims to cover some of the most recent advances in the field of materials for drug delivery systems (DDSs) and emphasizes the role that multifunctional materials play in advancing the performance of modern DDSs in the context of the most current challenges presented. The Roadmap is comprised of multiple sections, each of which introduces the status of the field, the current and future challenges faced, and a perspective of the required advances necessary for biomaterial science to tackle these challenges. It is our hope that this collective vision will contribute to the initiation of conversation and collaboration across all areas of multifunctional materials for DDSs. We stress that this article is not meant to be a fully comprehensive review but rather an up-to-date snapshot of different areas of research, with a minimal number of references that focus upon the very latest research developments.

Antibody-Mediated Nanodrug of Proteasome Inhibitor Carfilzomib Boosts the Treatment of Multiple Myeloma.

Multiple myeloma (MM) is the second most common hematological malignancy. For relapsed and refractory MM, a proteasome inhibitor, carfilzomib (CFZ), has become one of the few clinical options. CFZ suffers, nevertheless, metabolic instability and poor bioavailability and may induce severe cardiovascular and renal adverse events. Here, we report that daratumumab (Dar)-decorated polypeptide micelles (Dar-PMs) mediate the targeted delivery of CFZ to CD38-positive MM, effectively boosting its anti-MM efficacy. CFZ-loaded Dar-PMs (Dar-PMs-CFZ) exhibited an average diameter of ca. 80 nm and Dar density-dependent cell endocytosis and anti-MM activity, in which over 6-fold greater inhibitory effect to LP-1 and MM.1S MM cells than nontargeted PMs-CFZ control was achieved at a Dar density of 3.2 (Dar3.2-PMs-CFZ). Interestingly, Dar3.2-PMs-CFZ markedly enhanced the growth inhibition of orthotopic LP-1 MM in mice and significantly extended the median survival time compared with PMs-CFZ and free CFZ (95 days vs 60 and 54 days, respectively). In line with its high MM targetability and anti-MM efficacy, Dar3.2-PMs-CFZ revealed little toxic effects and effectively prevented osteolytic lesions. The antibody-targeted nanodelivery of a proteasome inhibitor appears to be an appealing strategy to treat multiple myeloma.

Three-Dimensional MXene-AgNP Hollow Spheres for In Situ Surface-Enhanced Raman Scattering Detection of Catalysis Reactions.

MXenes are attractive candidates in the fields of surface-enhanced Raman scattering (SERS) and catalysis. However, most of the current studies on MXenes are based on blocks and nanosheets, limiting their SERS and catalytic properties. Herein, we have prepared 3D MXene hollow spheres wrapped with silver nanoparticles (Ti3C2-AgNP HSs) using a sacrificial template method, which exhibits excellent sensitivity with a low detection limit due to good light-trapping capability of the hollow sphere and strong localized surface plasmon resonance (LSPR) effect of AgNPs. Furthermore, it shows outstanding photocatalytic performance and realizes in situ SERS monitoring of the 4-nitrobenzenethiol (4-NTP) to 4-aminothiophenol (4-ATP) catalysis reaction. The finite-difference time-domain (FDTD) simulations confirm that 3D Ti3C2-AgNP hollow structures have stronger hot spots than 3D solid structures and higher SERS sensitivity for molecule detection. Therefore, it promises to be an excellent bifunctional material for highly sensitive SERS detection and the in situ monitoring of catalytic reactions.

Rational discovery of dual FLT3/HDAC inhibitors as a potential AML therapy.

Acute myeloid leukemia (AML) patients often experience poor therapeutic outcomes and relapse after treatment with single-target drugs, representing the urgent need of new therapies. Simultaneous inhibition of multiple oncogenic signals is a promising strategy for tumor therapy. Previous studies have reported that concomitant inhibition of Fms-like tyrosine kinase 3 (FLT3) and histone deacetylases (HDACs) can significantly improve the therapeutic efficacy for AML. Herein, a series of novel dual FLT3/HDAC inhibitors were developed through a rational structure-based drug design strategy for the first time. Among them, multiple compounds showed potent and equivalent inhibitory activities against FLT3-ITD and HDAC1, with the representative compound 63 selectively inhibiting HDAC class I (HDAC1/2/3/8) and IIB isoforms (HDAC6) related to tumorigenesis, and intensively blocking proliferation of MV4-11 cells. The antiproliferation activity was proven to depend on the dual inhibition of FLT3 and HDAC1. Mechanism assays demonstrated that 63 prohibited both FLT3 and HDAC pathways, induced apoptosis and arrested cell cycle in MV4-11 cells in a dose-dependent manner. In summary, this study validated the therapeutic potential of a kind of dual FLT3/HDAC inhibitors for AML and provided novel compounds for further biological investigation on concomitant inhibition of FLT3/HDAC pathways. Additionally, the structure-based drug design strategy described herein may provide profound enlightenment for developing superior anti-AML drugs.

Hydrophobic tag-based protein degradation: Development, opportunity and challenge.

Targeted protein degradation (TPD) has emerged as a promising approach for drug development, particularly for undruggable targets. TPD technology has also been instrumental in overcoming drug resistance. While some TPD molecules utilizing proteolysis-targeting chimera (PROTACs) or molecular glue strategies have been approved or evaluated in clinical trials, hydrophobic tag-based protein degradation (HyT-PD) has also gained significant attention as a tool for medicinal chemists. The increasing number of reported HyT-PD molecules possessing high efficiency in degrading protein and good pharmacokinetic (PK) properties, has further fueled interest in this approach. This review aims to present the design rationale, hydrophobic tags in use, and diverse mechanisms of action of HyT-PD. Additionally, the advantages and disadvantages of HyT-PD in protein degradation are discussed. This review may help inspire the development of more HyT-PDs with superior drug-like properties for clinical evaluation.