Dihydroartemisinin decreases pre-existing neutralizing antibodies against adeno-associated virus in challenged mice.

Introduction: The high prevalence of pre-existing neutralizing antibodies (NAbs) against adeno-associated virus (AAV) poses a major obstacle to in vivo gene therapy. Current immunosuppressive (IS) strategies, such as corticosteroids, are limited by toxicity and adverse effects. To explore safer alternatives, we evaluated dihydroartemisinin (DHA), a synthetic derivative of artemisinin inspired by traditional Chinese medicine (TCM), as a potential IS agent.

Rational design of NAMPT-based dual inhibitors with improved drug-like and pharmacokinetic properties for cancer treatment.

While PD-1/PD-L1 immunotherapy has demonstrated significant clinical efficacy, current small-molecule inhibitors are limited by suboptimal oral bioavailability (F < 10 %) due to unfavorable physicochemical properties. To address this challenge, we developed bifunctional inhibitors that simultaneously target NAMPT (nicotinamide phosphoribosyltransferase) and PD-L1, leveraging NAMPT's critical role in immunometabolic reprogramming. The lead compound T8 exhibited potent dual-target inhibition, with an IC of 63 nM against PD-L1 and 0.

Research Progress in Targeting GSPT1: Molecular Glues, Bifunctional Degraders, and Antibody-Enabled Molecular Glues for Cancer Therapy.

G1 to S phase transition 1 (GSPT1, also known as eRF3a) is a crucial translation termination factor that plays a vital role in acute myeloid leukemia (AML) and MYC-driven lung cancer. Degrading GSPT1 can induce apoptosis in cancer cells and reduce their viability, thus making GSPT1 a potential therapeutic target. This perspective aims to introduce the current research status of the mechanism of molecular glues targeting GSPT1, summarize the recent progress in and challenges for existing molecular glues, bifunctional degraders, and antibody-enabled molecular glues targeting GSPT1, and outline the development strategies for targeting GSPT1 in the treatment of cancer.

Discovery of Small Molecule PD-L1 Inhibitors via Optimization of Solvent-Interaction Region for Cancer Immunotherapy.

Despite extensive research, the topic of anti-PD-L1 small-molecule inhibitors remains elusive. Herein, we report the design, synthesis, and bioevaluation of a series of small molecule PD-L1 inhibitors via optimization of the solvent-interaction region. Among them, compound GJ19 showed the most potent anti-PD-L1 effects with an IC of 32.

Comprehensive secretome profiling and CRISPR screen identifies SFRP1 as a key inhibitor of epidermal progenitor proliferation.

Secreted proteins are crucial for the structure and functions of the human epidermis, but the full repertoire of the keratinocyte secretome has not been experimentally defined. In this study, we performed mass spectrometry on conditioned media from primary human keratinocytes, identifying 406 proteins with diverse roles in adhesion, migration, proliferation, proteolysis, signal transduction, and innate immunity. To leverage this new dataset, we developed a novel colony formation assay-based CRISPR screen to investigate the functions of uncharacterized secreted proteins on epidermal stem cells.

Oleanolic acid inhibits M2 macrophage polarization and potentiates anti-PD-1 therapy in hepatocellular carcinoma by targeting miR-130b-3p-PTEN-PI3K-Akt signaling and glycolysis.

Background: Hypoxia promotes M2 polarization of macrophages and the formation of the immunosuppressive tumor microenvironment (TME) in hepatocellular carcinoma (HCC). Oleanolic acid (OA) has shown great potential in the treatment of HCC. However, the mechanisms of macrophage M2 polarization in hypoxic tumor TME and the regulating effect of OA is still unclear.

Discovery of bifunctional small molecules targeting PD-L1/VISTA with favorable pharmacokinetics for cancer immunotherapy.

In this work, we designed and synthesized a series of bifunctional PD-L1/VISTA (V-domain immunoglobulin suppressor of T-cell activation) small molecule inhibitors. Among them, S8 showed acceptable PD-L1 inhibitory effects (IC = 1.4 μM, HTRF assay) and VISTA binding activity (K = 2.

Discovery of Novel and Highly Potent Dual PD-L1/Histone Deacetylase 6 Inhibitors with Favorable Pharmacokinetics for Cancer Immunotherapy.

A series of novel PD-L1/HDAC6 dual inhibitors were designed and synthesized, and compound was identified as the most potent candidate, which demonstrated excellent and selective HDAC6 inhibitory activity (IC = 78 nM, SI > 1282), and high anti-PD-1/PD-L1 activity (IC = 26.8 nM). Further studies showed that could bind with high affinity to PD-L1 and HDAC6 protein.

Paeoniflorin inhibits chronic restraint stress-induced progression of hepatocellular carcinoma through suppressing norepinephrine-induced activation of hepatic stellate cells via SRC/AKT/ERK pathways.

Ethnopharmacological Relevance: Paeoniae Radix Alba (the root of Paeonia lactiflora Pall.) is a well-known Chinese herb medicine used for alleviating depression and anxiety. Paeoniflorin (PF), an active ingredient of Paeoniae Radix Alba, is usually used in emotion and inflammation-related diseases.

Discovery of highly potent dual GSPT1/BRD4 degraders with anti-AML activity.

Translational readthrough (TR) regulation has emerged as a promising therapeutic strategy for cancer treatment. Utilizing a constructed monoclonal cell line AG-9, designed for screening compounds that induce TR, we identified a BRD4-targeted PROTAC molecule, dBET57, that promotes TR by degrading GSPT1. Notably, dBET57 exhibited significant antiproliferative activity against acute myeloid leukemia (AML) and non-Hodgkin lymphoma (NHL) cells across a diverse panel of tumor cell lines.

Research progress in bifunctional small molecules for cancer immunotherapy.

Immunotherapy has become one of the most revolutionary modalities for cancer treatment with the approval of many anti-PD-L1 (programmed cell death-ligand 1)/PD-1 (programmed cell death-1) monoclonal antibodies (mAbs). However, anti-PD-L1/PD-1 mAbs suffer from several drawbacks including limited clinical efficacy (∼20 %), poor pharmacokinetics, and the development of immune resistance. Hence, the search for PD-1/PD-L1-based combination therapies and other PD-L1-based bifunctional small molecule modulators [e.

Research progress in DNA damage response (DDR)-targeting modulators: From hits to clinical candidates.

In recent years, synthetic lethality has been regarded as a sound example of cancer treatment. Identifying a growing number of synthetic lethality targets has led to a substantial broadening of the application of synthetic lethality, well beyond the PAPR inhibitors employed for treating tumors with BRCA1/2 deficiencies. Especially, molecular targets within the DDR have furnished inhibitor sources and have rapidly advanced to clinical trials.

Recent advances in developing targeted protein degraders.

Targeted protein degradation (TPD) represents a promising therapeutic approach, encompassing several innovative strategies, including but not limited to proteolysis targeting chimeras (PROTACs), molecular glues, hydrophobic tag tethering degraders (HyTTD), and lysosome-targeted chimeras (LYTACs). Central to TPD are small molecule ligands, which play a critical role in mediating the degradation of target proteins. This review summarizes the current landscape of small molecule ligands for TPD molecules.

Protein arginine methyltransferase 7 modulators in disease therapy: Current progress and emerged opportunity.

Protein arginine methyltransferase 7 (PRMT7) is an essential epigenetic and post-translational regulator in eukaryotic organisms. Dysregulation of PRMT7 is intimately related to multiple types of human diseases, particularly cancer. In addition, PRMT7 exerts multiple effects on cellular processes such as growth, migration, invasion, apoptosis, and drug resistance in various cancers, making it as a promising target for anti-tumor therapeutics.

Small molecule inhibitors targeting PD-L1, CTLA4, VISTA, TIM-3, and LAG3 for cancer immunotherapy (2020-2024).

Cancer immunotherapy, leveraging antibodies, excels in targeting efficacy but faces hurdles in tissue penetration, oral delivery, and prolonged half-life, with costly production and risk of adverse immunogenic effects. In contrast, small molecule immuno-oncology agents provide favorable pharmacokinetic properties and benign toxicity profiles. These agents are well-positioned to address the limitations of antibody-based immunotherapies, augment existing treatment modalities, and achieve synergistic effects when combined with antibodies.

Jiedu recipe, a compound Chinese herbal medicine, suppresses hepatocellular carcinoma metastasis by inhibiting the release of tumor-derived exosomes in a hypoxic microenvironment.

Objective: Tumor-derived exosomes (TDEs) play crucial roles in intercellular communication. Hypoxia in the tumor microenvironment enhances secretion of TDEs and accelerates tumor metastasis. Jiedu recipe (JR), a traditional Chinese medicinal formula, has demonstrated efficacy in preventing the metastasis of hepatocellular carcinoma (HCC).

Small-Molecule Modulators Targeting Coactivator-Associated Arginine Methyltransferase 1 (CARM1) as Therapeutic Agents for Cancer Treatment: Current Medicinal Chemistry Insights and Emerging Opportunities.

Overexpression of coactivator associated arginine methyltransferase 1 (CARM1) is associated with various diseases including cancer. Therefore, CARM1 has emerged as an attractive therapeutic target and a drug response biomarker for anticancer drug discovery. However, the development of conventional CARM1 inhibitors has been hampered by their limited clinical efficacy, acquired resistance, and inability to inhibit nonenzymatic functions of CARM1.

Overview of the PRMT6 modulators in cancer treatment: Current progress and emerged opportunity.

Protein Arginine Methyltransferase 6 (PRMT6) is a Type I PRMT enzyme that plays a role in the epigenetic regulation of gene expression by methylating histone and non-histone proteins. It is also involved in various cellular processes, including alternative splicing, DNA repair, and cell signaling. Furthermore, PRMT6 exerts multiple effects on cellular processes such as growth, migration, invasion, apoptosis, and drug resistance in various cancers, positioning it as a promising target for anti-tumor therapeutics.

Bioactive sphingolipids as emerging targets for signal transduction in cancer development.

Sphingolipids, crucial components of cellular membranes, play a vital role in maintaining cellular structure and signaling integrity. Disruptions in sphingolipid metabolism are increasingly implicated in cancer development. Key bioactive sphingolipids, such as ceramides, sphingosine-1-phosphate (S1P), ceramide-1-phosphate (C1P), and glycosphingolipids, profoundly impact tumor biology.

Geochronology, geochemistry, and geological significance of early Jurassic intrusive rocks in the Lesser Xing'an- Zhangguangcai Range, northeast China.

The Lesser Xing'an-Zhangguangcai Range of northeast China is located in the eastern segment of the Central Asian Orogenic Belt (CAOB), which records intense magmatism during the Mesozoic. The petrogenesis and geodynamic setting of the Early Jurassic intrusive rocks in this region are unclear. In this paper, we present new zircon U-Pb age and whole-rock geochemical data for these intrusive rocks to investigate their origins and tectonic setting.

Superfast, large-scale harvesting of cellulose molecules via ethanol pre-swelling engineering of natural fibers.

Cellulose molecules, as the basic unit of biomass cellulose, have demonstrated advancements in versatile engineering and modification of cellulose toward sustainable and promising materials in our low-carbon society. However, harvesting high-quality cellulose molecules from natural cellulosic fibers (CF) remains challenging due to strong hydrogen bonds and unique crystalline structure, which limit solvents (such as ionic liquid, IL) transport and diffusion within CF, making the process energy/time-intensively. Herein, we superfast and sustainably engineer biomass fibers into high-performance cellulose molecules via ethanol pre-swelling of CF followed by IL treatment in the microwave (MW) system.

Overview of class I HDAC modulators: Inhibitors and degraders.

Class I histone deacetylases (HDACs) are closely associated with the development of a diverse array of diseases, including cancer, neurodegenerative disorders, HIV, and inflammatory diseases. Considering the essential roles in tumorigenesis, class I HDACs have emerged as highly desirable targets for therapeutic strategies, particularly in the field of anticancer drug development. However, the conventional class I HDAC inhibitors faced several challenges such as acquired resistance, inherent toxicities, and limited efficacy in inhibiting non-enzymatic functions of HDAC.