A patent review of SCF E3 ligases inhibitors for cancer：Structural design, pharmacological activities and structure-activity relationship.

Currently, as the largest family of E3 ubiquitin ligases, Skp1-Cullin 1-F-box (SCF) E3 ligase complexes have attracted extensive attention. Among SCF complexes, Skp2, ß-TrCP, and FBXW7 have undergone extensive research on their structures and functions. Previous studies suggest Skp2, ß-TrCP, and FBXW7 are overexpressed in numerous cancers. Thus, the SCF E3 ligase complex has become a significant target for the development of anti-cancer drugs. Over the past few decades, a variety of anti-tumor inhibitors targeting the SCF E3 ligase complex have been attempted. However, since almost none of the SCF E3 ligase inhibitors passed clinical trials, the design and synthesis of the new inhibitors are needed. Here, we will introduce the structure and function of Skp2, ß-TrCP, and FBXW7, their connections with cancer development, the relevant in vitro and in vivo activities, selectivity, structure-activity relationships, and the therapeutic or preventive application of small molecule inhibitors targeting these three F-box proteins reported in the patent (2010-present). This information will help develop drugs targeting the SCF E3 ubiquitin ligase, providing new strategies for future cancer treatments.

Targeting NTCP for liver disease treatment: A promising strategy.

The sodium taurocholate co-transporting polypeptide (NTCP), a bile acids transporter, has been identified as a new therapeutic target for the treatment of liver disease. This paper thoroughly investigates the function of NTCP for regulating bile acid regulation, its correlation with hepatitis B and D infections, and its association with various liver diseases. Additionally, in this review we examine recent breakthroughs in creating NTCP inhibitors and their prospective applications in liver disease treatment. While this review emphasizes the promising potential of targeting NTCP, it concurrently underscores the need for broader and more detailed research to fully understand the long-term implications and potential side effects associated with NTCP inhibition.

Associations between body fat anthropometric indices and mortality among individuals with metabolic syndrome.

BACKGROUND: The distribution of body fat and metabolic health may contribute to the onset of metabolic syndrome (MetS), but the associations between body fat anthropometric indices (AIs) and mortality in individuals with MetS remain unclear. METHODS: Participants aged 18 years or older with MetS were recruited from the NHANES 1999-2018. The body fat anthropometric indices included the a body shape index (ABSI), body roundness index (BRI), cardiometabolic index (CMI), visceral adiposity index (VAI), waist triglyceride index (WTI), lipid accumulation product (LAP), atherogenic index of plasma (AIP), and triglyceride‒glucose (TyG) index. MetS was defined according to the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATPIII) criteria. Mortality data were obtained from the National Death Index through December 31, 2019. RESULTS: Data were collected from 8,379 individuals with MetS, with a median follow-up of 8.5 years, of whom 1,698 died from all causes and 568 from the CCD. The random survival forest (RSF) analysis indicated that the ABSI had the strongest predictive power for both all-cause mortality and CCD mortality among the eight body fat AIs. After adjusting for multiple variables, the ABSI was found to be linearly and positively associated with all-cause and CCD mortality in individuals with MetS. Participants in the highest quartile of ABSI had an increased risk of all-cause (HR = 1.773 [1.419-2.215]) and CCD (HR = 1.735 [1.267-2.375]) mortality compared with those in the lowest quartile. Furthermore, the ABSI predicted areas under the curve (AUCs) of 0.735, 0.723, 0.718, and 0.725 for all-cause mortality at 3, 5, 10, and 15 years, respectively, and 0.774, 0.758, 0.725, and 0.715 for CCD mortality, respectively. CONCLUSION: Among eight body fat AIs, the ABSI exhibited the strongest predictive power for mortality in individuals with MetS. Higher ABSI values significantly increased all-cause mortality and CCD mortality in participants with MetS.

Progress of ATM inhibitors: Opportunities and challenges.

Ataxia-telangiectasia mutated (ATM) was first discovered in patients with AT (ataxia telangiectasia), which is characteristic with cerebellar degeneration, immunodeficiency, being susceptible to malignant tumors and sensitive to radiation. ATM kinase could detect DNA double-strand breaks and play a vital role in the DNA damage response. Inhibiting the function of ATM could sensitize tumor cells to both ionizing radiation (IR) and chemotherapy, as well as improve the chemoresistance and radioresistance observed in some patients. As such, ATM is a novel and important target for the cancer therapy. We reviewed ATM inhibitors reported in the last two decades, focusing on their development process, structure-activity relationships, inhibitory efficacy, pharmacokinetics and pharmacodynamics characteristics in the preclinical and clinical studies. We summarized the clinical value of ATM inhibitors in tumors and some neurodegenerative diseases, as well as the main challenges to the development of the drugs, providing directions and references for the future development of ATM inhibitors.

Recent advancements in the small-molecule drugs for hepatocellular carcinoma (HCC): Structure-activity relationships, pharmacological activities, and the clinical trials.

BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world and the sixth leading cause of cancer death worldwide, and it is urgent to find safe and effective drugs for treatment. As an important therapeutic method, small-molecule drugs are continually being updated to achieve improved therapeutic effects. The purpose of this study was to investigate the structural effects of various FDA-listed small-molecule drugs sorafenib, cabozantinib, lenvatinib, and regorafenib on the corresponding HCC targets and possible structural optimization methods, and to explore the mechanism for identifying potential therapeutic drugs that offer better efficacy and fewer side effects. METHODS: The structure-activity relationship, pharmacological actions, and clinical applications of small-molecule drugs were reviewed by referencing MEDLINE, Web of Science, CNKI, and other databases, summarizing and integrating the relevant content. RESULTS: The results showed that small-molecule drugs can inhibit HCC primarily by forming hydrogen bonds with Glu885, Asp1046, and Cys919 on the HCC target. HCC can be targeted by inhibiting the activation of multiple pathways, blocking the conduction of downstream signaling, and reducing the formation of tumor blood vessels. In general, small-molecule drugs primarily target four key receptors in HCC: VEGFR, PDGFR, EGFR, and FGFR, to achieve effective treatment. CONCLUSIONS: By revealing their structure-activity relationships, pharmacological actions, and clinical trials, small-molecule drugs can offer broad prospects for the development of new medications.

Novel antibody-drug conjugates based on DXd-ADC technology.

In recent years, antibody-drug conjugate (ADC) technology, which uses monoclonal antibodies (mAbs) to specifically deliver effective cytotoxic payloads to tumor cells, has become a promising method of tumor targeted therapy. ADCs are a powerful class of biopharmaceuticals that link antibodies targeting specific antigens and small molecule drugs with potent cytotoxicity via a linker, thus enabling selective destruction of cancer cells while minimizing systemic toxicity. DXd is a topoisomerase I inhibitor that induces DNA damage leading to cell cycle arrest, making it an option for ADC payloads. The DXd-ADC technology, developed by Daiichi Sankyo, is a cutting-edge platform that produces a new generation of ADCs with improved therapeutic metrics and has shown significant therapeutic potential in various types of cancer. This review provides a comprehensive assessment of drugs developed with DXd-ADC technology, with a focus on mechanisms of action, pharmacokinetics studies, preclinical data, and clinical outcomes for DS-8201a, U3-1402, DS-1062a, DS-7300a, DS-6157a, and DS-6000a. By integrating existing data, we aim to provide valuable insights into the current therapeutic status and future prospects of these novel agents.

Pathogenesis of cardiovascular diseases: effects of mitochondrial CF6 on endothelial cell function.

Cardiovascular disease (CVD) stands as a predominant global cause of morbidity and mortality, necessitating effective and cost-efficient therapies for cardiovascular risk reduction. Mitochondrial coupling factor 6 (CF6), identified as a novel proatherogenic peptide, emerges as a significant risk factor in endothelial dysfunction development, correlating with CVD severity. CF6 expression can be heightened by CVD risk factors like mechanical force, hypoxia, or high glucose stimuli through the NF-κB pathway. Many studies have explored the CF6-CVD relationship, revealing elevated plasma CF6 levels in essential hypertension, atherosclerotic cardiovascular disease (ASCVD), stroke, and preeclampsia patients. CF6 acts as a vasoactive and proatherogenic peptide in CVD, inducing intracellular acidosis in vascular endothelial cells, inhibiting nitric oxide (NO) and prostacyclin generation, increasing blood pressure, and producing proatherogenic molecules, significantly contributing to CVD development. CF6 induces an imbalance in endothelium-dependent factors, including NO, prostacyclin, and asymmetric dimethylarginine (ADMA), promoting vasoconstriction, vascular remodeling, thrombosis, and insulin resistance, possibly via C-src Ca2+ and PRMT-1/DDAH-2-ADMA-NO pathways. This review offers a comprehensive exploration of CF6 in the context of CVD, providing mechanistic insights into its role in processes impacting CVD, with a focus on CF6 functions, intracellular signaling, and regulatory mechanisms in vascular endothelial cells.

Recent advances in anti-inflammation via AMPK activation.

Inflammation is a complex physiological phenomenon, which is the body's defensive response, but abnormal inflammation can have adverse effects, and many diseases are related to the inflammatory response. AMPK, as a key sensor of cellular energy status, plays a crucial role in regulating cellular energy homeostasis and glycolipid metabolism. In recent years, the anti-inflammation effect of AMPK and related signalling cascade has begun to enter everyone's field of vision - not least the impact on metabolic diseases. A great number of studies have shown that anti-inflammatory drugs work through AMPK and related pathways. Herein, this article summarises recent advances in compounds that show anti-inflammatory effects by activating AMPK and attempts to comment on them.

Bacteroides ovatus alleviates high-fat and high-cholesterol -induced nonalcoholic fatty liver disease via gut-liver axis.

Gut microbiota acts as a critical regulator in the development of nonalcoholic fatty liver disease (NAFLD), making probiotics a promise therapeutic strategy. Studies are needed to identify beneficial Bacteroides strains against NAFLD. Bacteroides ovatus (B. ovatus) may also exhibit therapy effect on NAFLD. The aim of this work was to evaluate the effect of B. ovatus on NAFLD and examine the mechanism. C57BL/6 J male mice were randomly divided into three groups: a control group (NCD) that received control standard diet, a model group (M) with high-fat and high-cholesterol (HFHC) diet, and M_Bo group that was fed HFFC supplemented with B. ovatus. Treatment with B. ovatus could reduce body weight, prevent hepatic steatohepatitis and liver injury. Mechanistically, B. ovatus induced changes of gut microbial diversity and composition, characterized by a decreased Firmicutes/Bacteroidetes (F/B) ratio in M_Bo group mice, a lower abundance of Proteobacteria, Verrucomicrobiota at phylum level and Ruminococcus_torques_group, Ruminococcus_gauvreauii_group, Erysipelatoclostridium at genus level, simultaneously a remarkablely higher fecal abundance of Lachnospiraceae_NK4A136_group, norank_f__Oscillospiraceae, Colidextribacter. Compared with M group, mice treated with B. ovatus showed an markedly altered fecal short chain fatty acids (SCFAs), a decline in serum levels of lipopolysaccharide (LPS), CD163, IL-1ß, TNF-α, reduced macrophages in livers. Additionally, B. ovatus treatment caused downregulation of genes involved in denovo lipogenesis (such as Srebfl, Acaca, Scd1, Fasn), which was accompanied by the upregulation of genes related with fatty acid oxidation (such as Ppara). In conclusion, this study provides evidence that B. ovatus could ameliorate NAFLD by modulating the gut-liver axis.

Strategies for developing µ opioid receptor agonists with reduced adverse effects.

Opioids are currently the most effective and widely used painkillers in the world. Unfortunately, the clinical use of opioid analgesics is limited by serious adverse effects. Many researchers have been working on designing and optimizing structures in search of novel µ opioid receptor(MOR) agonists with improved analgesic activity and reduced incidence of adverse effects. There are many strategies to develop MOR drugs, mainly focusing on new low efficacy agonists (potentially G protein biased agonists), MOR agonists acting on different Gα subtype, targeting opioid receptors in the periphery, acting on multiple opioid receptor, and targeting allosteric sites of opioid receptors, and others. This review summarizes the design methods, clinical applications, and structure-activity relationships of small-molecule agonists for MOR based on these different design strategies, providing ideas for the development of safer novel opioid ligands with therapeutic potential.

Progress in the development of modulators targeting Frizzleds.

The Frizzleds (FZDs) receptors on the cell surface belong to the class F of G protein-coupled receptors (GPCRs) which are the major receptors of WNT protein that mediates the classical WNT signaling pathway and other non-classical pathways. Besides, the FZDs also play a core role in tissue regeneration and tumor occurrence. With the structure and mechanism of FZDs activation becoming clearer, a series of FZDs modulators (inhibitors and agonists) have been developed, with the hope of bringing benefits to the treatment of cancer and degenerative diseases. Most of the FZDs inhibitors (small molecules, antibodies or designed protein inhibitors) block WNT signaling through binding to the cysteine-rich domain (CRD) of FZDs. Several small molecules impede FZDs activation by targeting to the third intracellular domain or the transmembrane domain of FZDs. However, three small molecules (FZM1.8, SAG1.3 and purmorphamine) activate the FZDs through direct interaction with the transmembrane domain. Another type of FZDs agonists are bivalent or tetravalent antibodies which activate the WNT signaling via inducing FZD-LRP5/6 heterodimerization. In this article, we reviewed the FZDs modulators reported in recent years, summarized the critical molecules' discovery processes and the elucidated relevant structural and pharmacological mechanisms. We believe the summaried molecular mechanisms of the relevant modulators could provide important guidance and reference for the future development of FZD modulators.

Discovery of Novel Proteolysis-Targeting Chimera Molecules as Degraders of Programmed Cell Death-Ligand 1 for Breast Cancer Therapy.

The immune checkpoint blockade represents a pivotal strategy for tumor immunotherapy. At present, various programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) monoclonal antibodies have been successfully applied to tumor treatment. Additionally, numerous small molecule inhibitors of the PD-1/PD-L1 interaction have also been developed, with some advancing into clinical trials. Here, a novel PD-L1 proteolysis-targeting chimera (PROTAC) library was designed and synthesized utilizing the PD-L1 inhibitor BMS202 and the E3 ligand PG as foundational components. Among these, we identified a highly potent molecule PA8 for PD-L1 degradation in 4T1 cells (DC50 = 0.609 µM). Significantly, compound PA8 potentially inhibits 4T1 cell growth both in vitro and in vivo. Further mechanistic studies revealed that PA8 effectively promoted the immune activation of model mice. Thus, these results suggest that PA8 could be a novel strategy for cancer immunotherapy in the 4T1 tumor model. Although PA8 exhibits weaker degradation activity in some human cancer cells, it still provides a certain basis for further research on PD-L1 PROTAC.

Recent advances of honokiol：pharmacological activities, manmade derivatives and structure-activity relationship.

Honokiol (HNK) is a typical natural biphenyl polyphenol compound. It has been proven to have a wide range of biological activities, including pharmacological effects such as anti-cancer, anti-inflammatory, neuroprotective, and antimicrobial. However, due to the poor stability, water solubility, and bioavailability of HNK, HNK has not been used in clinical treatment. This article reviews the latest research on the pharmacological activity of HNK and summarizes the HNK derivatives designed and improved by several researchers. Reviewing these contents could promote the research process of HNK and guide the design of better HNK derivatives for clinical application in the future.

Recent development of VEGFR small molecule inhibitors as anticancer agents: A patent review (2021-2023).

VEGFR, a receptor tyrosine kinase inhibitor (TKI), is an important regulatory factor that promotes angiogenesis and vascular permeability. It plays a significant role in processes such as tumor angiogenesis, tumor cell invasion, and metastasis. VEGFR is mainly composed of three subtypes: VEGFR-1, VEGFR-2, and VEGFR-3. Among them, VEGFR-2 is the crucial signaling receptor for VEGF, which is involved in various pathological and physiological functions. At present, VEGFR-2 is closely related to a variety of cancers, such as non-small cell lung cancer (NSCLC), Hepatocellular carcinoma, Renal cell carcinoma, breast cancer, gastric cancer, glioma, etc. Consequently, VEGFR-2 serves as a crucial target for various cancer treatments. An increasing number of VEGFR inhibitors have been discovered to treat cancer, and they have achieved tremendous success in the clinic. Nevertheless, VEGFR inhibitors often exhibit severe cytotoxicity, resistance, and limitations in indications, which weaken the clinical therapeutic effect. In recent years, many small molecule inhibitors targeting VEGFR have been identified with anti-drug resistance, lower cytotoxicity, and better affinity. Here, we provide an overview of the structure and physiological functions of VEGFR, as well as some VEGFR inhibitors currently in clinical use. Also, we summarize the in vivo and in vitro activities, selectivity, structure-activity relationship, and therapeutic or preventive use of VEGFR small molecule inhibitors reported in patents in the past three years (2021-2023), thereby presenting the prospects and insights for the future development of targeted VEGFR inhibitors.

AAA237, an SKP2 inhibitor, suppresses glioblastoma by inducing BNIP3-dependent autophagy through the mTOR pathway.

BACKGROUND: Glioblastoma (GBM) is the most common brain tumor with the worst prognosis. Temozolomide is the only first-line drug for GBM. Unfortunately, the resistance issue is a classic problem. Therefore, it is essential to develop new drugs to treat GBM. As an oncogene, Skp2 is involved in the pathogenesis of various cancers including GBM. In this study, we investigated the anticancer effect of AAA237 on human glioblastoma cells and its underlying mechanism. METHODS: CCK-8 assay was conducted to evaluate IC50 values of AAA237 at 48, and 72 h, respectively. The Cellular Thermal Shift Assay (CETSA) was employed to ascertain the status of Skp2 as an intrinsic target of AAA237 inside the cellular milieu. The EdU-DNA synthesis test, Soft-Agar assay and Matrigel assay were performed to check the suppressive effects of AAA237 on cell growth. To identify the migration and invasion ability of GBM cells, transwell assay was conducted. RT-qPCR and Western Blot were employed to verify the level of BNIP3. The mRFP-GFP-LC3 indicator system was utilized to assess alterations in autophagy flux and investigate the impact of AAA237 on the dynamic fusion process between autophagosomes and lysosomes. To investigate the effect of compound AAA237 on tumor growth in vivo, LN229 cells were injected into the brains of mice in an orthotopic model. RESULTS: AAA237 could inhibit the growth of GBM cells in vitro. AAA237 could bind to Skp2 and inhibit Skp2 expression and the degradation of p21 and p27. In a dose-dependent manner, AAA237 demonstrated the ability to inhibit colony formation, migration, and invasion of GBM cells. AAA237 treatment could upregulate BNIP3 as the hub gene and therefore induce BNIP3-dependent autophagy through the mTOR pathway whereas 3-MA can somewhat reverse this process. In vivo, the administration of AAA237 effectively suppressed the development of glioma tumors with no side effects. CONCLUSION: Compound AAA237, a novel Skp2 inhibitor, inhibited colony formation, migration and invasion of GBM cells in a dose-dependent manner and time-dependent manner through upregulating BNIP3 as the hub gene and induced BNIP3-dependent autophagy through the mTOR pathway therefore it might be a viable therapeutic drug for the management of GBM.

Unleashing the Potential of Camptothecin: Exploring Innovative Strategies for Structural Modification and Therapeutic Advancements.

Camptothecin (CPT) is a potent anti-cancer agent targeting topoisomerase I (TOP1). However, CPT has poor pharmacokinetic properties, causes toxicities, and leads to drug resistance, which limit its clinical use. In this paper, to review the current state of CPT research. We first briefly explain CPT's TOP1 inhibition mechanism and the key hurdles in CPT drug development. Then we examine strategies to overcome CPT's limitations through structural modifications and advanced delivery systems. Though modifications alone seem insufficient to fully enhance CPT's therapeutic potential, structure-activity relationship analysis provides insights to guide optimization of CPT analogs. In comparison, advanced delivery systems integrating controlled release, imaging capabilities, and combination therapies via stimulus-responsive linkers and targeting moieties show great promise for improving CPT's pharmacological profile. Looking forward, multifaceted approaches combining selective CPT derivatives with advanced delivery systems, informed by emerging biological insights, hold promise for fully unleashing CPT's anti-cancer potential.

Emerging phosphodiesterase inhibitors for treatment of neurodegenerative diseases.

Neurodegenerative diseases (NDs) cause progressive loss of neuron structure and ultimately lead to neuronal cell death. Since the available drugs show only limited symptomatic relief, NDs are currently considered as incurable. This review will illustrate the principal roles of the signaling systems of cyclic adenosine and guanosine 3',5'-monophosphates (cAMP and cGMP) in the neuronal functions, and summarize expression/activity changes of the associated enzymes in the ND patients, including cyclases, protein kinases, and phosphodiesterases (PDEs). As the sole enzymes hydrolyzing cAMP and cGMP, PDEs are logical targets for modification of neurodegeneration. We will focus on PDE inhibitors and their potentials as disease-modifying therapeutics for the treatment of Alzheimer's disease, Parkinson's disease, and Huntington's disease. For the overlapped but distinct contributions of cAMP and cGMP to NDs, we hypothesize that dual PDE inhibitors, which simultaneously regulate both cAMP and cGMP signaling pathways, may have complementary and synergistic effects on modifying neurodegeneration and thus represent a new direction on the discovery of ND drugs.