Pharmacological inhibition of EZH2 using a covalent inhibitor suppresses human ovarian cancer cell migration and invasion.

Metastasis is the cause of poor prognosis in ovarian cancer (OC). Enhancer of Zeste homolog 2 (EZH2), a histone-lysine N-methyltransferase enzyme, promotes OC cell migration and invasion by regulating the expression of tissue inhibitor of metalloproteinase-2 (TIMP2) and matrix metalloproteinases-9 (MMP9). Hence, we speculated that EZH2-targeting therapy might suppress OC migration and invasion. In this study, the expression of EZH2, TIMP2, and MMP9 in OC tissues and cell lines was analyzed using The Cancer Genome Atlas (TCGA) database and western blotting, respectively. The effects of SKLB-03220, an EZH2 covalent inhibitor, on OC cell migration and invasion were investigated using wound-healing assays, Transwell assays, and immunohistochemistry. TCGA database analysis confirmed that the EZH2 and MMP9 mRNA expression was significantly higher in OC tissues, whereas TIMP2 expression was significantly lower than that in normal ovarian tissues. Moreover, EZH2 negatively correlated with TIMP2 and positively correlated with MMP9 expression. In addition to the anti-tumor activity of SKLB-03220 in a PA-1 xenograft model, immunohistochemistry results showed that SKLB-03220 markedly increased the expression of TIMP2 and decreased the expression of MMP9. Additionally, wound-healing and Transwell assays showed that SKLB-03220 significantly inhibited the migration and invasion of both A2780 and PA-1 cells in a concentration-dependent manner. SKLB-03220 inhibited H3K27me3 and MMP9 expression and increased TIMP2 expression in PA-1 cells. Taken together, these results indicate that the EZH2 covalent inhibitor SKLB-03220 inhibits metastasis of OC cells by upregulating TIMP2 and downregulating MMP9, and could thus serve as a therapeutic agent for OC.

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.

[Interaction between root exudates of medicinal plants and rhizosphere microorganisms and its application in ecological planting of Chinese medicinal materials].

The rhizosphere is an important place for material exchange between medicinal plants and soil. Root exudates are the medium of material and signal exchange between plants and soil and are the key factors in the regulation of rhizosphere microecology. Rhizosphere microorganisms are an important part of the rhizosphere microecology of medicinal plants, and the interaction between root exudates and rhizosphere microorganisms has an important influence on the growth and quality formation of medicinal plants. Rational utilization of the interaction between root exudates and rhizosphere microorganisms of medicinal plants is one of the important ways to ensure the healthy growth of medicinal plants and promote the development of ecological planting of Chinese medicinal materials. In the paper, the research status of root exudates and rhizosphere microorganisms of medicinal plants in recent years was summarized. The interaction mechanism between root exudates and rhizosphere microorganisms of medicinal plants, as well as the influence of rhizosphere microorganisms on the growth of medicinal plants, were analyzed. In addition, the advantages and promoting effects of intercropping ecological planting mode on rhizosphere microecology of medicinal plants and quality improvement of Chinese medicinal materials were explained, providing a good basis for the study of the interaction among medicinal plants, microorganisms, and soil. Furthermore, it could produce important theoretical and practical significance for the ecological planting and sustainable utilization of medicinal plants.

Tetraphenylethylene-Based Hydrogen-Bonded Organic Frameworks (HOFs) with Brilliant Fluorescence.

By synergistically employing four key strategies: (I) introducing tetraphenylethylene groups as the central core unit with aggregation-induced emission (AIE) properties, (II) optimizing the π-conjugated length by extending the building block branches, (III) incorporating flexible groups containing ethylenic bonds, and (IV) applying crystal engineering to attain dense stacking mode and highly twisty conformation, we successfully synthesized a series of hydrogen-bonded organic frameworks (HOFs) exhibiting exceptional one/two-photon excited fluorescence. Notably, when utilizing the fluorescently superior building block L2, HOF-LIFM-7 and HOF-LIFM-8 exhibiting high quantum yields (QY) of 82.1 % and 77.1 %, and ultrahigh two-photon absorption (TPA) cross-sections of 148959.5 GM and 123901.1 GM were achieved. These materials were successfully employed in one and two-photon excited lysosome-targeting cellular imaging. It is believed that this strategy, combining building block optimization and crystal engineering, holds significant potential for guiding the development of outstanding fluorescent HOF materials.

One/Two-Photon-Excited ESIPT-Attributed Coordination Polymers with Wide Temperature Range and Color-Tunable Long Persistent Luminescence.

The multiple metastable excited states provided by excited-state intramolecular proton transfer (ESIPT) molecules are beneficial to bring temperature-dependent and color-tunable long persistent luminescence (LPL). Meanwhile, ESIPT molecules are intrinsically suitable to be modulated as D-π-A structure to obtain both one/two-photon excitation and LPL emission simultaneously. Herein, we report the rational design of a dynamic CdII coordination polymer (LIFM-106) from ESIPT ligand to achieve the above goals. By comparing LIFM-106 with the counterparts, we established a temperature-regulated competitive relationship between singlet excimer and triplet LPL emission. The optimization of ligand aggregation mode effectively boost the competitiveness of the latter. In result, LIFM-106 shows outstanding one/two-photon excited LPL performance with wide temperature range (100-380 K) and tunable color (green to red). The multichannel radiation process was further elucidated by transient absorption and theoretical calculations, benefiting for the application in anti-counterfeiting systems.

Thermally Activated Fluorescence vs Long Persistent Luminescence in ESIPT-Attributed Coordination Polymer.

Excited-state intramolecular proton transfer (ESIPT) molecules demonstrating specific enol-keto tautomerism and the related photoluminescence (PL) switch have wide applications in displaying, sensing, imaging, lasing, etc. However, an ESIPT-attributed coordination polymer showing alternative PL between thermally activated fluorescence (TAF) and long persistent luminescence (LPL) has never been explored. Herein, we report the assembly of a dynamic Cd(II) coordination polymer (LIFM-101) from the ESIPT-type ligand, HPI2C (5-(2-(2-hydroxyphenyl)-4,5-diphenyl-1H-imidazol-1-yl)isophthalic acid). For the first time, TAF and/or color-tuned LPL can be achieved by controlling the temperature under the guidance of ESIPT excited states. Noteworthily, the twisted structure of the HPI2C ligand in LIFM-101 achieves an effective mixture of the higher-energy excited states, leading to ISC (intersystem crossing)/RISC (reverse intersystem crossing) energy transfer between the high-lying keto-triplet state (Tn(K*)) and the first singlet state (S1(K*)). Meanwhile, experimental and theoretical results manifest the occurrence probability and relevance among RISC, ISC, and internal conversion (IC) in this unique ESIPT-attributed coordination polymer, leading to the unprecedented TAF/LPL switching mechanism, and paving the way for the future design and application of advanced optical materials.

Focus on the classical and non-classical functions of EZH2: Guide the development of inhibitors and degraders.

Enhancer of zeste homologue 2 (EZH2, also known as KMT6A) is found to be a member of the histone lysine methyltransferase family. An increasing number of studies have shown that in addition to methylating histones, EZH2 plays a vital role in a variety of ways. The methylated substrates of EZH2 also include GATA4, AR/AR-related proteins, STAT3, Talin protein, and RORα. Meanwhile, EZH2 has been reported to form complexes with some proteins to perform other important biological functions as well as methylation. These complexes include: the EZH2-RelA-RelB complex, EZH2-ER-ß-catenin complex, and ß-catenin-PAF-EZH2-Mediator complex. Herein, we focus on the classical and non-classical functions of EZH2, and summarize anti-EZH2 therapeutic strategies. Finally, we highlight that understanding the physiological and pathological functions of EZH2 in specific indications can help the development of inhibitors or degraders.

High-Temperature and Dynamic RGB (Red-Green-Blue) Long-Persistent Luminescence in an Anti-Kasha Organic Compound.

Organic LPL (long-persistent luminescence) materials have sparked extensive research interest due to the ultralong-lived triplet states. Although numerous organic LPL materials have been reported, most of the triplet emission was static and monotonous. Therefore, LPL materials with dynamic triplet emission are urgently required. A triamino-s-triazine derivative 1 with dynamic LPL was fabricated. The single-crystal structure shows that the abundant intermolecular interactions and small free volume restrict the molecular motion and avoid the quenchers. Spectral and theoretical calculations upheld the existence of multiple excited states in 1, and the migration of electrons between multiple excited states is very sensitive to external stimuli. By modulating the stimulus, the residence of electrons in different triplet states can be manipulated to achieve RGB LPL. Importantly, blue LPL was achieved by manipulating the anti-Kasha emission. And the red LPL can still be observed at high temperature.

One and Two-Photon Excited Fluorescence Optimization of Metal-Organic Frameworks with Symmetry-Reduced AIEgen-Ligand.

By designing a tetraphenylethylene (TPE)-based AIEgen-ligand with reduced symmetry, we obtained two alkaline-earth metal-based MOFs (LIFM-102 and LIFM-103) with dense packing structures and low porosity as proved by single-crystal X-ray diffraction and CO2 sorption data. Excitingly, the desolvated MOFs with rigid environment and reduced lattice free solvent exhibit high quantum yields (QY, 64.9 % and 79.4 %) and excellent two-photon excited photoluminescence (TPA cross-sections, 2946.6 GM and 2899.0 GM), while maintaining the external-stimuli-responsive properties suitable for anticounterfeit fields. The effect of ligand conformation was validated by comparing the structure and fluorescence properties of the samples before and after desolvation and further verified by theoretical calculations. This work expands the study on TPE-cored materials to symmetry-reduced ligand and might bring forward novel structures and excellent photoluminescent properties in the future.

Design and synthesis of (E)-1,2-diphenylethene-based EZH2 inhibitors.

Enhancer of zeste homolog 2 (EZH2) serves as the catalytic subunit of the polycomb repression complex 2 (PRC2), which is implicated in cancer progression metastasis and poor prognosis. Based on our EZH2 inhibitor SKLB1049 with low nanomolar activity, we extended the "tail" region to get a series of (E)-1,2-diphenylethene derivatives as novel EZH2 inhibitors. SAR exploration and preliminary assessment led to the discovery of the potent novel EZH2 inhibitor 9b (EZH2WT IC50 = 22.0 nM). Compound 9b inhibited the proliferation of WSU-DLCL2 and SU-DHL-4 cell lines (IC50 = 1.61 µM and 2.34 µM, respectively). The biological evaluation showed that 9b was a potent inhibitor for wild-type EZH2 and greatly reduced the overall levels of H3K27me3 in a concentration-dependent manner. Further study indicated that 9b could significantly induce apoptosis of SU-DHL-4 cells. These findings indicated that 9b would be an attractive lead compound for further optimization and evaluation.

Design, synthesis and biological evaluation of a novel tubulin inhibitor SKLB0565 targeting the colchicine binding site.

A series of 3-(((9H-purin-6-yl) amino) methyl) pyridin-2(1H)-one derivatives were designed, synthesized and confirmed as tubulin polymerization inhibitors. All compounds were evaluated for their anti-proliferative activities on three colorectal carcinoma (CRC) cell lines. Among these compounds, SKLB0565 displayed noteworthy potency against eight CRC cell lines with IC50 values ranging from 0.012 µM and 0.081 µM. Besides, SKLB0565 inhibited tubulin polymerization, caused G2/M phase cell cycle arrest, depolarized mitochondria and induced cell apoptosis in CRC cells. Furthermore, SKLB0565 suppressed cell migration and disrupted the capillary tube formation of human umbilical vein endothelial cells (HUVECs). Our data clarified that SKLB0565 is a promising anti-tubulin agent for CRC therapy which is worthy of further evaluation.

Synthesis and biological evaluation of benzomorpholine derivatives as novel EZH2 inhibitors for anti-non-small cell lung cancer activity.

The histone lysine methyltransferase EZH2 has been reported to play important roles in cancer aggressiveness, metastasis and poor prognosis. In this study, a series of benzomorpholine derivatives were synthesized and biologically evaluated as EZH2 inhibitors. The target compounds were obtained in good yields from 3-amino-5-bromo-2-hydroxybenzoic acid via cyclization, Suzuki coupling and amidation as the key steps. A preliminary optimization study led to the discovery of several potent novel EZH2 inhibitors (6b, 6c, 6x and 6y). Moreover, 6y inhibited the A549 and NCI-H1975 cell lines (IC50 = 1.1 µM and 1.1 µM, respectively). Further studies indicated that 6y can reduce EZH2 expression in intact cells and cause cell arrest in the G2/M phase.

Recent developments in the catalytic conversion of cellulose.

The increasing demand for energy has led to the development of biomass conversion technologies. As the most abundant biomass on Earth, cellulose is generally chosen as the primary research target for biomass conversion. In this review, gasification and pyrolysis of cellulose are briefly discussed and hydrolysis is then considered in detail. Moreover, many new developments and applications are introduced in cellulose conversion in recent years. Among these technologies, heterogeneous catalysis, hydrolysis in ionic liquid and hydrolysis by hot-compressed water exhibit a promising potential in cellulose conversion. Therefore, they are well recognized as powerful, fast and efficient techniques, becoming the focus of intensive research.

Transformational Modulation of Fluorescence to Room Temperature Phosphorescence in Metal-Organic Frameworks with Flexible C-S-C Bonds.

Photoluminescent metal-organic frameworks (MOFs) have been a subject of considerable interest for many years. However, the regulation of excited states of MOFs at the single crystal level remains restricted due to a lack of control methods. The singlet-triplet emissive property can be significantly influenced by crystal conformational distortions. This review introduces an intelligent responsive MOF material, denoted as LIFM-SHL-3a, characterized by flexible C-S-C bonds. LIFM-SHL-3a integrates elastic structural dynamics with fluorescence and room temperature phosphorescence (RTP) modulation under heating conditions. The deformable carbon-sulfur bond essentially propels the distortion of molecular conformation and alters the stacking mode, as illustrated by single-crystal-to-single-crystal transformation detection. The deformation of flexible C-S-C bonds leads to different noncovalent interactions in the crystal system, thereby achieving modulation of the fluorescence (F) and RTP bands. In the final state structure, the ratio of fluorescence is 66.7%, and the ratio of RTP is 32.6%. This stands as a successful demonstration of modulating F/RTP within the dynamic MOF, unlocking potential applications in optical sensing and beyond. Especially, a PL thermometer with a relative sensitivity of 0.096-0.104%·K-1 in the range of 300-380 K and a H2S probe with a remarkably low LOD of 125.80 nM can be obtained using this responsive MOF material of LIFM-SHL-3a.

Thermal control over phosphorescence or thermally activated delayed fluorescence in a metal-organic framework.

By integrating a tailor-made donor-acceptor (D-A) ligand in a metal-organic framework (MOF), a material with unprecedented features emerges. The ligand combines a pair of cyano groups as acceptors with four sulfanylphenyls as donors, which expose each a carboxylic acid as coordination sites. Upon treatment with zinc nitrate in a solvothermal synthesis, the MOF is obtained. The new material combines temperature-assisted reverse intersystem crossing (RISC) and intersystem crossing (ISC). As these two mechanisms are active in different temperature windows, thermal switching between their characteristic emission wavelengths is observed for this material. The two mechanisms can be activated by both, one-photon absorption (OPA) and two-photon absorption (TPA) resulting in a large excitement window ranging from ultraviolet (UV) over visible light (VL) to near infrared (NIR). Furthermore, the emission features of the material are pH sensitive, such that its application potential is demonstrated in a first ammonia sensor.

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.

Design, synthesis and antitumor activity of a novel FGFR2-selective degrader to overcome resistance of the FGFR2V564F gatekeeper mutation based on a pan-FGFR inhibitor.

Aberrant activation of fibroblast growth factor receptors (FGFRs) contributes to the development and progression of multiple types of cancer. Although many FGFR inhibitors have been approved by the FDA, their long-term therapeutic efficacy is hampered by acquired resistance to gatekeeper mutations and low subtype selectivity. FGFR2 has been found to be frequently amplified or mutated in many tumors. In this study, we designed several PROTACs with different E3 ligands based on LY2874455. By screening the length of the linker and the binding site in various degraders, we obtained a novel and highly efficient FGFR2-selective degrader 28e (DC50 = 0.645 nM, DCmax = 86 %). Compound 28e selectively degraded FGFR2 and essentially avoided degradation of FGFR1,3,4 isoforms (DC50 > 300 nM). Compound 28e significantly inhibited the proliferation of FGFR2-overexpressing cell lines, including KATOIII, SNU16, and AN3CA (IC50 = 0.794 nM/0.207 nM/4.626 nM), comparable to parental inhibitors. At the same time, the preferred compound showed superiority over the parental inhibitor in kinase inhibitory activity against the gatekeeper mutant isoform FGFR2V564F (IC50 = 0.121 nM). In summary, we identified 28e as a novel selective degrader of FGFR2 with high potency and high potential to overcome resistance to gatekeeper mutation. The discovery of 28e provides new evidence for the strategy of pan-inhibitor-based development of selective degrading agents.

Multifunctional fluorescent probe for simultaneous revealing Cys and ONOO- dynamic correlation in the ferroptosis.

Ferroptosis is a type of lipid peroxidation-induced apoptosis brought on by imbalances in iron metabolism and redox. It involves both the thiol-associated anti-ferroptosis pathway and the excessive buildup of reactive oxygen species (ROS), which stimulates the ferroptosis pathway. Determining the precise control mechanism of ferroptosis requires examining the dynamic connection between reactive sulfur species (RSS) and ROS. Cysteine (Cys) and peroxynitrite (ONOO-) are highly active redox species in organisms and play dynamic roles in the ferroptosis process. In this study, a coumarin dye was conjugated with specific response sites for Cys and ONOO-, enabling the simultaneous detection of Cys and ONOO- through the green and red fluorescence channels, respectively (λem = 498 nm for Cys and λem = 565 nm for ONOO-). Using the probe LXB, we monitored the changes in Cys and ONOO- levels in the ferroptosis pathway induced by erastin. The results demonstrate a significant generation of ONOO- and a noticeable decrease in intracellular Cys levels at the beginning upon erastin treatment and finally maintains a relatively low level. This study presents the first probe to investigate the intracellular redox modulation and control between Cys and ONOO- during ferroptosis, providing valuable insights into the potential mutual correlation between Cys and ONOO- in this process.

A TICT-AIE activated dual-channel fluorescence-on probe to reveal the dynamics mechanosensing of lipid droplets during ferroptosis.

Mechanical forces play a crucial role in cellular processes, including ferroptosis, a form of regulated cell death associated with various diseases. However, the mechanical aspects of organelle lipid droplets (LDs) during ferroptosis are poorly understood. In this study, we designed and synthesized a fluorescent probe, TPE-V1, to enable real-time monitoring of LDs' viscosity using a dual-channel fluorescence-on model (red channel at 617 nm and NIR channel at 710 nm). The fluorescent imaging of using TPE-V1 was achieved due to the integrated mechanisms of the twisted intramolecular charge transfer (TICT) and aggregation-induced emission (AIE). Through dual-emission channel fluorescence imaging, we observed the enhanced mechanical energy of LDs triggering cellular mechanosensing, including ferroptosis and cell deformation. Theoretical calculations confirmed the probe's behavior, showing that high-viscosity media prevented the rotation processes and restored fluorescence quenching in low viscosity. These findings suggest that our TICT-TPE design strategy provides a practical approach to study LDs' mechanical properties during ferroptosis. This development enhances our understanding of the interplay between mechanical forces and LDs, contributing to the knowledge of ferroptotic cell death and potential therapeutic interventions targeting dysregulated cell death processes.

Insight into Structure-Activity Relationship of New Compounds for Breast Cancer Treatment.

BACKGROUND: Breast cancer has always been a vicious disease that threatens female health. Although the existing surgery, radiotherapy, chemotherapy, and kinase-targeted drugs have achieved certain effects, there are still many shortcomings. Novel compounds used to treat breast cancer, particularly TNBC, are eagerly being discovered. METHODS: More than 100 novel compounds that show anti-breast cancer growth were compiled from public databases. The compound design strategies, structure-activity relationship research, and activity evaluation methods have also been reviewed. RESULTS: These novel anti-breast cancer compounds can be divided into mechanisms of action: kinase inhibitors, epigenetic inhibitors, dual inhibitors, degraders, metal complexes, etc. The design strategies mainly include conformational constraint, scaffold-hopping, merging key pharmacophores, etc. Structure-activity relationship studies of these new compounds mainly focus on increasing activity, improving selectivity, increasing membrane permeability, reducing toxicity, improving pharmacokinetic properties, etc. Conclusion: Through the structural optimization of kinase inhibitors, microtubule-targeted drugs, and metal complexes, it is expected to obtain more advantageous breast cancer treatment drugs. It cannot be ignored that epigenetic inhibitors, dual inhibitors and degraders may bring new breast cancer treatment strategies.