Tunneling Interpenetrative Lithium Ion Conduction Channels in Polymer-in-Ceramic Composite Solid Electrolytes.

Polymer-in-ceramic composite solid electrolytes (PIC-CSEs) provide important advantages over individual organic or inorganic solid electrolytes. In conventional PIC-CSEs, the ion conduction pathway is primarily confined to the ceramics, while the faster routes associated with the ceramic-polymer interface remain blocked. This challenge is associated with two key factors: (i) the difficulty in establishing extensive and uninterrupted ceramic-polymer interfaces due to ceramic aggregation; (ii) the ceramic-polymer interfaces are unresponsive to conducting ions because of their inherent incompatibility. Here, we propose a strategy by introducing polymer-compatible ionic liquids (PCILs) to mediate between ceramics and the polymer matrix. This mediation involves the polar groups of PCILs interacting with Li+ ions on the ceramic surfaces as well as the interactions between the polar components of PCILs and the polymer chains. This strategy addresses the ceramic aggregation issue, resulting in uniform PIC-CSEs. Simultaneously, it activates the ceramic-polymer interfaces by establishing interpenetrating channels that promote the efficient transport of Li+ ions across the ceramic phase, the ceramic-polymer interfaces, and the intervening pathways. Consequently, the obtained PIC-CSEs exhibit high ionic conductivity, exceptional flexibility, and robust mechanical strength. A PIC-CSE comprising poly(vinylidene fluoride) (PVDF) and 60 wt % PCIL-coated Li3Zr2Si2PO12 (LZSP) fillers showcasing an ionic conductivity of 0.83 mS cm-1, a superior Li+ ion transference number of 0.81, and an elongation of ∼300% at 25 °C could be produced on meter-scale. Its lithium metal pouch cells show high energy densities of 424.9 Wh kg-1 (excluding packing films) and puncture safety. This work paves the way for designing PIC-CSEs with commercial viability.

Development of Phenyl-substituted Isoindolinone- and Benzimidazole-type Cereblon Ligands for Targeted Protein Degradation.

Thalidomide, pomalidomide and lenalidomide, collectively referred to as immunomodulatory imide drugs (IMiDs), are frequently employed in proteolysis-targeting chimeras (PROTACs) as cereblon (CRBN) E3 ligase-recruiting ligands. However, their molecular glue properties that co-opt the CRL4CRBN to degrade its non-natural substrates may lead to undesired off-target effects for the IMiD-based PROTAC degraders. Herein, we reported a small library of potent and cell-permeable CRBN ligands, which exert high selectivity over the well-known CRBN neo-substrates of IMiDs by structure-based design. They were further utilized to construct bromodomain-containing protein 4 (BRD4) degraders, which successfully depleted BRD4 in the tested cells. Overall, we reported a series of functionalized CRBN recruiters that circumvent the promiscuity from traditional IMiDs, and this study is informative to the development of selective CRBN-recruiting PROTACs for many other therapeutic targets.

Targeted degradation of extracellular secreted and membrane proteins.

Targeted protein degradation (TPD) involving chimeric molecules has emerged as one of the most promising therapeutic modalities in recent years. Among various reported TPD strategies, proteolysis-targeting chimeras (PROTACs) stand out as a significant breakthrough in small-molecule drug discovery and have garnered the most attention to date. However, PROTACs are mainly capable of depleting intracellular proteins. Given that many important therapeutic targets such as cytokines, growth factors, and numerous receptors are membrane proteins or secreted extracellularly, there is interest in the development of novel strategies to degrade these protein categories. We review advances in this emerging area and provide insights to enhance the development of novel TPDs targeting extracellular proteins.

Development of Potent and Selective Coactivator-Associated Arginine Methyltransferase 1 (CARM1) Degraders.

CARM1 is amplified or overexpressed in many cancer types, and its overexpression correlates with poor prognosis. Potent small-molecule inhibitors for CARM1 have been developed, but the cellular efficacy of the CARM1 inhibitors is limited. We herein report the development of the proteolysis targeting chimera (PROTAC) for CARM1, which contains a CARM1 ligand TP-064, a linker, and a VHL E3 ligase ligand. Compound 3b elicited potent cellular degradation activity (DC50 = 8 nM and Dmax > 95%) in a few hours. Compound 3b degraded CARM1 in VHL- and proteasome-dependent manner and was highly selective for CARM1 over other protein arginine methyltransferases. CARM1 degradation by 3b resulted in potent downregulation of CARM1 substrate methylation and inhibition of cancer cell migration in cell-based assays. Thus, CARM1 PROTACs can be used to interrogate CARM1's cellular functions and potentially be developed as therapeutic agents for targeting CARM1-driven cancers.

Dynamic Kinetic Stereoselective Glycosylation via RhII and Chiral Phosphoric Acid-Cocatalyzed Carbenoid Insertion to the Anomeric OH Bond for the Synthesis of Glycoconjugates.

Chemical synthesis of glycoconjugates is essential for studying the biological functions of carbohydrates. We herein report an efficient approach for the stereoselective synthesis of challenging α-linked glycoconjugates via a RhII /chiral phosphoric acid (CPA)-cocatalyzed dynamic kinetic anomeric O-alkylation of sugar-derived lactols via carbenoid insertion to the anomeric OH bond. Notably, we observed excellent anomeric selectivity, excellent diastereoselectivity, broad substrate scope, and high efficiency for this glycosylation reaction by exploring various parameters of the cocatalytic system. DFT calculations suggested that the anomeric selectivity was mainly determined by steric interactions between the C2-carbon of the carbohydrate and the phenyl group of the metal carbenoid, while π/π interactions with the C2-OBn substituent on the carbohydrate substrate play a significant role for diastereoselectivity at the newly generated stereogenic center.

A Modular Chemistry Platform for the Development of a Cereblon E3 Ligase-Based Partial PROTAC Library.

Proteolysis targeting chimeras (PROTACs) are a promising therapeutic strategy to selectively promote the degradation of protein targets by exploiting the ubiquitin-proteasome system. Among the limited number of E3 ligase ligands discovered for the PROTAC technology, ligands of cereblon (CRBN) E3 ligase, such as pomalidomide, thalidomide, or lenalidomide, are the most frequently used for the development of PROTACs. Our group previously reported that a phenyl group could be tolerated on the C4-position of lenalidomide as the ligand of CRBN to develop PROTACs. Herein, we report a modular chemistry platform for the efficient attachment of various ortho-, meta-, and para-substituted phenyls to the C4-position of the lenalidomide via Suzuki cross-coupling reaction, which allows the systematic investigation of the linker effect for the development of PROTACs against any target. We examined the substrate scope by preparing twelve lenalidomide-derived CRBN E3 ligase ligands with different linkers.

A platform for the rapid synthesis of molecular glues (Rapid-Glue) under miniaturized conditions for direct biological screening.

Molecular glues, functioning via inducing degradation of the target protein while having similar molecular weight as traditional small molecule drugs, are emerging as a promising modality for the development of therapeutic agents. However, the development of molecular glues is limited by the lack of general principles and systematic methods. Not surprisingly, most molecular glues have been identified serendipitously or through phenotypic screening of large libraries. However, the preparation of large and diverse molecular glue libraries is not an easy task and requires extensive resources. We previously developed platforms for rapid synthesis of proteolysis targeting chimeras (PROTACs) that can be used directly for biological screening with minimal resources. Herein, we report a platform of rapid synthesis of molecular glues (Rapid-Glue) via a micromolar scale coupling reaction between hydrazide motif on the E3 ligase ligands and commercially available aldehydes with diverse structures. A pilot library of 1520 compounds is generated under miniaturized conditions in a high throughput manner without any further manipulation including purification after the synthesis. Through this platform, we identified two highly selective GSPT1 molecular glues through direct screening in cell-based assays. Three additional analogues were prepared from readily available starting materials by replacing the hydrolytic labile acylhydrazone linker with a more stable amide linker based on the two hits. All three analogues showed significant GSPT1 degradation activity and two of them possess comparable activity to the corresponding hit. The feasibility of our strategy is thus verified. Further studies by increasing the diversity and size of the library followed by appropriate assays will likely yield distinct molecular glues targeting novel neo-substrates.

Development of Oligomeric Mannose-6-phosphonate Conjugates for Targeted Protein Degradation.

Lysosome targeting chimeras (LYTACs) are a new protein degradation strategy that has recently emerged. LYTACs utilize the native cell internalization process in the body to target and degrade therapeutically relevant extracellular proteins via the lysosomal pathways. The first lysosomal internalization receptor recently used for LYTACs is the mannose-6-phosphate receptor (M6PR). M6PR is expressed across most cell types, making it ideal for internalization and degradation of numerous extracellular proteins. Herein, we report the development of a series of structurally well-defined mannose-6-phosphonate (M6Pn)-peptide conjugates that are capable of linking to a variety of targeting ligands for proteins of interest and successfully internalizing and degrading those proteins through M6PR. This will greatly facilitate the development of M6Pn based LYTACs for therapeutic applications.

Ferroptosis signaling promotes the release of misfolded proteins via exosomes to rescue ER stress in hepatocellular carcinoma.

Dysfunction of the ubiquitin‒proteasome system can induce sustained endoplasmic reticulum stress (ERS) and subsequent cell death. However, malignant cells have evolved multiple mechanisms to evade sustained ERS. Therefore, identification of the mechanisms through which tumor cells develop resistance to ERS is important for the therapeutic exploitation of these cells for drug-resistant tumors. Herein, we found that proteasome inhibitors could induce ERS, activate ferroptosis signaling, and thereby induce the adaptive tolerance of tumor cells to ERS. Mechanistically, the activation of ferroptosis signaling was found to promote the formation and secretion of exosomes containing misfolded and unfolded proteins, which resulted in rescuing ERS and promoting tumor cell survival. The inhibition of ferroptosis signaling synergized with bortezomib, a clinically used proteasome inhibitor, to suppress the viability of hepatocellular carcinoma cells in vitro and in vivo. The present findings reveal that ERS resistance can be driven by an ERS-ferroptosis signaling-exosome pathway and have important clinical implications for intracellular signaling, ER homeostasis and drug-resistant cancer therapy.

Development of Substituted Phenyl Dihydrouracil as the Novel Achiral Cereblon Ligands for Targeted Protein Degradation.

Glutarimides such as thalidomide, pomalidomide, and lenalidomide are the most frequently used ligands to recruit E3 ubiquitin ligase cereblon (CRBN) for the development of proteolysis-targeting chimeras (PROTACs). Due to the rapid and spontaneous racemization of glutarimides, most CRBN-recruiting PROTACs are synthesized as a mixture of racemates or diastereomers. Since the (S)-enantiomer is primarily responsible for binding to CRBN, the existence of the largely inactive (R)-enantiomer complicates the drug development process. Herein, we report that substituted achiral phenyl dihydrouracil (PDHU) can be used as a novel class of CRBN ligands for the development of PROTACs. Although the parent PDHU has a minimal binding affinity to CRBN, we found that some substituted PDHUs had a comparable binding affinity to lenalidomide. Structural modeling provided a further understanding of the molecular interactions between PDHU ligands and CRBN. PDHUs also have greater stability than lenalidomide. Finally, potent BRD4 degraders were developed by employing trisubstituted PDHUs.

Diptoindonesin G is a middle domain HSP90 modulator for cancer treatment.

HSP90 inhibitors can target many oncoproteins simultaneously, but none have made it through clinical trials due to dose-limiting toxicity and induction of heat shock response, leading to clinical resistance. We identified diptoindonesin G (dip G) as an HSP90 modulator that can promote degradation of HSP90 clients by binding to the middle domain of HSP90 (Kd = 0.13 ± 0.02 µM) without inducing heat shock response. This is likely because dip G does not interfere with the HSP90-HSF1 interaction like N-terminal inhibitors, maintaining HSF1 in a transcriptionally silent state. We found that binding of dip G to HSP90 promotes degradation of HSP90 client protein estrogen receptor α (ER), a major oncogenic driver protein in most breast cancers. Mutations in the ER ligand-binding domain (LBD) are an established mechanism of endocrine resistance and decrease the binding affinity of mainstay endocrine therapies targeting ER, reducing their ability to promote ER degradation or transcriptionally silence ER. Because dip G binds to HSP90 and does not bind to the LBD of ER, unlike endocrine therapies, it is insensitive to ER LBD mutations that drive endocrine resistance. Additionally, we determined that dip G promoted degradation of WT and mutant ER with similar efficacy, downregulated ER- and mutant ER-regulated gene expression, and inhibited WT and mutant cell proliferation. Our data suggest that dip G is not only a molecular probe to study HSP90 biology and the HSP90 conformation cycle, but also a new therapeutic avenue for various cancers, particularly endocrine-resistant breast cancer harboring ER LBD mutations.

Surface differences of oxide nanocrystals determined by geometry and exogenously coordinated water molecules.

Determining the different surfaces of oxide nanocrystals is key in developing structure-property relations. In many cases, only surface geometry is considered while ignoring the influence of surroundings, such as ubiquitous water on the surface. Here we apply 17O solid-state NMR spectroscopy to explore the facet differences of morphology-controlled ceria nanocrystals considering both geometry and water adsorption. Tri-coordinated oxygen ions at the 1st layer of ceria (111), (110), and (100) facets exhibit distinct 17O NMR shifts at dry surfaces while these 17O NMR parameters vary in the presence of water, indicating its non-negligible effects on the oxide surface. Thus, the interaction between water and oxide surfaces and its impact on the chemical environment should be considered in future studies, and solid-state NMR spectroscopy is a sensitive approach for obtaining such information. The work provides new insights into elucidating the surface chemistry of oxide nanomaterials.

Sertraline inhibits stress-induced tumor growth through regulating CD8 + T cell-mediated anti-tumor immunity.

Chronic stress has been reported to be associated with tumor initiation and progression. But the underlying mechanism and the specific role of tumor immunity in this process are still unknown. Herein, we applied the repeated restrain stress model in C57BL/6J mice and found that the tumor growth in stressed mice was accelerated compared with that in control mice. In addition, serotonin, also called 5-hydroxytryptamine (5-HT), in the serum of stressed mice was also elevated. Sertraline, a selective serotonin reuptake inhibitor used in the clinic, can restore the serum 5-HT level in stressed mice and restrain tumor growth. We further explored the distribution of major immune cells, including B lymphocytes cells, T lymphocytes, natural killer cells, dendritic cells, tumor-associated macrophages (TAM) and regulatory T cells (Treg). We found that the infiltration of CD8 + T cells in the tumor microenvironment (TME) decreased significantly in stressed mice. And the extra 5-HT treatment could further decrease the infiltration of CD8 + T cells in the TME. The expression of IFN-γ and Granular enzyme B (GzmB) in CD8 + T cells were also dropped in the stressed mice group, whereas the expression of programmed cell death protein 1 (PD-1) on CD8 + T cells was increased. The T cell deficiency induced by stress can be reversed by sertraline, indicating its promising role in strengthening the efficacy of anti-PDL1/PD-1 immunotherapy. The present study provides new mechanistic insights into the impact of chronic stress on antitumor immunity and implicates a novel combined immunotherapy strategy for cancer patients with chronic stress.

Development of selective FGFR1 degraders using a Rapid synthesis of proteolysis targeting Chimera (Rapid-TAC) platform.

Proteolysis Targeting Chimera (PROTAC) has emerged as a novel therapeutic strategy. The major bottleneck for the development of PROTACs is the need to screen multiple parameters to create an effective degrader. It often involves the synthesis of dozens to hundreds of compounds one by one through a tedious process. We have developed a two-stage approach that allows for the rapid synthesis of PROTACs (Rapid-TAC) using preassembled building blocks to screen multiple parameters simultaneously. We herein report the application of this method to the development of PROTACs for FGFR, a challenging membrane protein target. In the first stage, we prepared 24 potential PROTACs quickly from a hydrazide-containing FGFR inhibitor and our previously reported VHL and CRBN ligand library bearing various linkers and an aldehyde functional group. These 24 PROTACs were then directly used for screening in cellular assay for protein degradation. Multiple hits were identified from the initial screening. We then prepared the corresponding stable analogues by replacing the hydrolytic labile acylhydrazone motif with an amide in the second stage. Among them, PROTAC LG1188 was identified as a potent and selective FGFR1 degrader.

Accurate prediction of microvascular invasion occurrence and effective prognostic estimation for patients with hepatocellular carcinoma after radical surgical treatment.

BACKGROUND: Hepatocellular carcinoma (HCC) is the third most common cause of cancer death worldwide, with an overall 5-year survival rate of less than 18%, which may be related to tumor microvascular invasion (MVI). This study aimed to compare the clinical prognosis of HCC patients with or without MVI after radical surgical treatment, and further analyze the preoperative risk factors related to MVI to promote the development of a new treatment strategy for HCC. METHODS: According to the postoperative pathological diagnosis of MVI, 160 study patients undergoing radical hepatectomy were divided into an MVI-negative group (n = 68) and an MVI-positive group (n = 92). The clinical outcomes and prognosis were compared between the two groups, and then the parameters were analyzed by multivariate logistic regression to construct an MVI prediction model. Then, the practicability and validity of the model were evaluated, and the clinical prognosis of different MVI risk groups was subsequently compared. RESULT: There were no significant differences between the MVI-negative and MVI-positive groups in clinical baseline, hematological, or imaging data. Additionally, the clinical outcome comparison between the two groups presented no significant differences except for the pathological grading (P = 0.002) and survival and recurrence rates after surgery (P < 0.001). The MVI prediction model, based on preoperative AFP, tumor diameter, and TNM stage, presented superior predictive efficacy (AUC = 0.7997) and good practicability (high H-L goodness of fit, P = 0.231). Compared with the MVI high-risk group, the patients in the MVI low-risk group had a higher survival rate (P = 0.002) and a lower recurrence rate (P = 0.004). CONCLUSION: MVI is an independent risk factor for a poor prognosis after radical resection of HCC. The MVI prediction model, consisting of AFP, tumor diameter, and TNM stage, exhibits superior predictive efficacy and strong clinical practicability for MVI prediction and prognostication, which provides a new therapeutic strategy for the standardized treatment of HCC patients.

Practice of Multidisciplinary Collaborative Chain Management Model in Constructing Nursing Path for Acute Trauma Treatment.

Prompt and effective treatment is the key to improve the prognosis of patients with acute trauma, and nursing plays an important role. However, conventional nursing has many limitations. Some studies have pointed out that the multidisciplinary collaborative chain management model can optimize the emergency procedures, ensure the continuity of the emergency treatment process, and optimize the treatment details. This study analyzed the practice of constructing an acute trauma care pathway based on a multidisciplinary collaborative chain management model. The results showed that the application of the multidisciplinary collaborative chain management model in the construction of acute trauma treatment nursing paths can enhance the emergency efficiency and nursing treatment, prevent the occurrence of adverse events, and improve the prognosis of patients.

Proteolysis-targeting chimera (PROTAC) delivery system: advancing protein degraders towards clinical translation.

Proteolysis Targeting Chimeras (PROTACs), an emerging therapeutic entity designed to degrade target proteins by hijacking the ubiquitin-proteasome system, have the potential to revolutionize the healthcare industry. The broad applicability of this protein degradation strategy has been verified with a few E3 ligases and a variety of distinct targets through the construction of modular chimeric structures. Despite recent efforts to promote the use of PROTACs for clinical applications, most PROTACs do not make it beyond the preclinical stage of drug development. There are several reasons that prevent PROTACs from reaching the market, and the inadequate delivery to the target site is one of the most challenging hurdles. With the increasing need for accelerating the translational process, combining the concepts of PROTACs and delivery systems has been explored to enhance the in vivo performance of PROTACs. These improved delivery strategies can eliminate unfavorable physicochemical properties of PROTACs, improve their targetability, and decrease their off-target side effects. The integration of powerful PROTACs and versatile delivery systems will inaugurate a burgeoning orientation for the field of targeted protein degradation. In this review, we will survey the latest progress in improving the in vivo degradation efficacy of PROTACs through delivery strategies, outline design principles for PROTAC-based delivery systems, discuss the current challenges with PROTACs, and outlook future opportunities in this field.

A platform for the rapid synthesis of proteolysis targeting chimeras (Rapid-TAC) under miniaturized conditions.

Proteolysis targeting chimera (PROTAC) is one of the most frequently used technologies for targeted protein degradation. PROTACs are composed of target protein ligand, E3 ligase ligand and a linker between them. Traditional methods for the development of PROTACs involve step-by-step synthesis and are time consuming. Herein, we report a platform for the rapid synthesis of PROTACs (Rapid-TAC) via a traceless coupling reaction between ortho-phthalaldehyde (OPA) motif on the ligand of targeting protein and an amine fucntional group on the commercially available partial PROTAC library that is composed of different E3 ligase ligands and various types and lengths of linkers. Under our optimized miniaturized conditions, the full PROTACs can be synthesized in a high throughput manner and the products can be directly used for screening without any further manipulations including purification. We demonstrated the utility of this platform by quickly identifying active degraders for androgen receptor (AR) and BRD4 with DC50 of 41.9 nM and 8.9 nM, respectively. It is expected that this Rapid-TAC platform can be easily extended to many other targets, thus lowering the barrier to access this novel modelity for small molecule drug discovery and faciliate structure activity relationship studies.

In Silico Modeling and Scoring of PROTAC-Mediated Ternary Complex Poses.

Proteolysis targeting chimeras (PROTACs) are molecules that induce protein degradation via formation of ternary complexes between an E3 ubiquitin ligase and a target protein. The rational design of PROTACs requires accurate knowledge of the native configuration of the PROTAC-induced ternary complex. This study demonstrates that native and non-native ternary complex poses can be distinguished based on the pose occupancy time in MD, where native poses exhibit longer occupancy times at both room and higher temperatures. Candidate poses are generated by MD sampling and pre-ranked by classic MM/GBSA. A specific heating scheme is then applied to accelerate ternary pose departure, with the pose occupancy time and fraction being measured. This scoring identifies the native pose in all systems tested. Its success is partially attributed to the dynamic nature of pose departure analyses, which accounts for entropic effects typically neglected in the faster static scoring methods, while entropy plays a greater role in protein-protein than in protein-ligand systems.

Enhancing ionic conductivity in solid electrolyte by relocating diffusion ions to under-coordination sites.

Solid electrolytes are highly important materials for improving safety, energy density, and reversibility of electrochemical energy storage batteries. However, it is a challenge to modulate the coordination structure of conducting ions, which limits the improvement of ionic conductivity and hampers further development of practical solid electrolytes. Here, we present a skeleton-retained cationic exchange approach to produce a high-performance solid electrolyte of Li3Zr2Si2PO12 stemming from the NASICON-type superionic conductor of Na3Zr2Si2PO12. The introduced lithium ions stabilized in under-coordination structures are facilitated to pass through relatively large conduction bottlenecks inherited from the Na3Zr2Si2PO12 precursor. The synthesized Li3Zr2Si2PO12 achieves a low activation energy of 0.21 eV and a high ionic conductivity of 3.59 mS cm-1 at room temperature. Li3Zr2Si2PO12 not only inherits the satisfactory air survivability from Na3Zr2Si2PO12 but also exhibits excellent cyclic stability and rate capability when applied to solid-state batteries. The present study opens an innovative avenue to regulate cationic occupancy and make new materials.