Thienopyrimidine: A promising scaffold in the development of kinase inhibitors with anticancer activities.

Protein kinases represent a highly promising drug target, with over 80 drugs that target about two dozen different protein kinases have been approved by the US FDA, particularly in cancer treatment. Over the past decades, the unique structural characteristics of the thienopyrimidine ring system provide an adaptive platform for designing potent anticancer agents, especially various kinase inhibitors, which has attracted widespread attention. Some of these thienopyrimidines as anticancer kinase inhibitors have already been marketed or are currently undergoing clinical/preclinical studies for the treatment of cancers, such as Olmutinib, Pictilisib, SNS-314, PF-03758309, and Fimepinostat, highlighting the substantial advantages of the thienopyrimidine scaffold in the discovery of anticancer agents.

Discovery of 2,4-diaminopyrimidine derivatives as potent inhibitors of FAK capable of activating the Hippo pathway for the treatment of esophageal squamous cell carcinoma.

In this work, we report the discovery of 2,4-diaminopyrimidine derivatives bearing a urea moiety as FAK inhibitors capable of activating the Hippo pathway in Esophageal Squamous Cell Carcinoma (ESCC). Extensive structure-activity relationship studies were conducted based on the lead FAK inhibitor TAE-226 to enhance the inhibitory potency, and the most potent compound 8b (MY-1576) as a FAK inhibitor ultimately was identified. Compound MY-1576 exhibited potent FAK inhibitory activity, in vitro anticancer activities, and acceptable PK properties.

Discovery of novel thienopyridine indole derivatives as inhibitors of tubulin polymerization targeting the colchicine-binding site with potent anticancer activities.

Based on the molecular hybridization strategy, novel thienopyridine indole derivatives were designed and synthesized as tubulin polymerization inhibitors, and the in vitro antiproliferative potency on MGC-803, KYSE450 and HCT-116 cells was evaluated. Among them, compound 20b showed a broad-spectrum antiproliferative activity against 11 cancer cell lines, with IC values below 4 nmol/L. Notably, it demonstrated exceptional efficacy against MGC-803 (IC = 1.

Discovery of novel 2,4-diarylaminopyrimidine hydrazone derivatives as potent anti-thyroid cancer agents capable of inhibiting FAK.

In this work, thirty 2,4-diarylaminopyrimidine-based hydrazones were designed, synthesised, and their anti-thyroid cancer activity were explored. The majority of compounds exhibit moderate to excellent cytotoxic activity against FAK overexpressing TPC-1 cells, with IC values ranging from 0.113 to 1.

Perceptions of the role of dentists in human papillomavirus and COVID-19 vaccinations: Results of a cross-sectional validated survey of adults.

Background: Human papillomavirus (HPV) and COVID-19 are contagious diseases for which effective vaccines exist. Dental care professionals' involvement in vaccination campaigns for these conditions has been proposed, but there is a lack of understanding of dentists' roles in vaccination, specifically assessing patients' attitudes around dentists as vaccinators for HPV and COVID-19.

Methods: Using a cross-sectional design and convenience sampling, a 12-item validated survey was distributed to community members to determine perceptions about dentists' roles in vaccination for HPV and COVID-19.

Discovery of novel pyrazolo[1,5-a]pyrimidine derivatives as potent reversal agents against ABCB1-mediated multidrug resistance.

The P-glycoprotein (ABCB1)-mediated multidrug resistance (MDR) has emerged as a significant impediment to the efficacy of cancer chemotherapy in clinical therapy, which could promote the development of effective agents for MDR reversal. In this work, we reported the exploration of novel pyrazolo [1,5-a]pyrimidine derivatives as potent reversal agents capable of enhancing the sensitivity of ABCB1-mediated MDR MCF-7/ADR cells to paclitaxel (PTX). Among them, compound 16q remarkably increased the sensitivity of MCF-7/ADR cells to PTX at 5 μM (IC = 27.

Targeting focal adhesion kinase (FAK) in cancer therapy: A recent update on inhibitors and PROTAC degraders.

Focal adhesion kinase (FAK) is considered as a pivotal intracellular non-receptor tyrosine kinase, and has garnered significant attention as a promising target for anticancer drug development. As of early 2024, a total of 12 drugs targeting FAK have been approved for clinical or preclinical studies worldwide, including three PROTAC degraders. In recent three years (2021-2023), significant progress has been made in designing targeted FAK anticancer agents, including the development of a novel benzenesulfofurazan type NO-releasing FAK inhibitor and the first-in-class dual-target inhibitors simultaneously targeting FAK and HDACs.

Synthesis and biological evaluation of 4-phenyl-5-quinolinyl substituted isoxazole analogues as potent cytotoxic and tubulin polymerization inhibitors against ESCC.

The identification of chemically different inhibitors that target the colchicine site of tubulin is still of great value for cancer treatment. Combretastatin A-4(CA-4), a naturally occurring colchicine-site binder characterized by its structural simplicity and biological activity, has served as a structural blueprint for the development of novel analogues with improved safety and therapeutic efficacy. In this study, a library of forty-eight 4-phenyl-5-quinolinyl substituted triazole, pyrazole or isoxazole analouges of CA-4, were synthesized and evaluated for their cytotoxicity against Esophageal Squamous Cell Carcinoma (ESCC) cell lines.

Discovery of the 2,4-disubstituted quinazoline derivative as a novel neddylation inhibitor for tumor therapy.

Overactivation of neddylation has been found in a number of common human tumor-related diseases. In recent years, targeting the neddylation pathway has become an appealing anti-cancer strategy, and it is critical to find neddylation inhibitors with novel structures and higher efficacy. Here, we present the discovery of novel inhibitors of the NEDD8-activating enzyme (NAE) and their antitumor activity in vitro.

Discovery of novel tranylcypromine-based derivatives as LSD1 inhibitors for gastric cancer treatment.

As an important epigenetic regulator, histone lysine specific demethylase 1 (LSD1) has become an attractive target for the discovery of anticancer agents. In this work, a series of tranylcypromine-based derivatives were designed and synthesized. Among them, compound 12u exhibited the most potent inhibitory potency on LSD1 (IC = 25.

Phloroglucinol inhibits oxytocin-induced contraction in rat gastric circular muscle and uterine smooth muscle.

Phloroglucinol is commonly used to alleviate dysmenorrhoea and stomach cramps. However, there is little evidence of phloroglucinol in the mechanism of primary dysmenorrhoea (PD) development. In this study, a PD rat model was established.

Associations of perfluoroalkyl and polyfluoroalkyl substances with gestational hypertension and blood pressure during pregnancy: A cohort study.

Previous studies have reported inconsistent associations between perfluoroalkyl and polyfluoroalkyl substances (PFAS) and gestational hypertension (GH) and blood pressure (BP) during pregnancy. Herein, we aimed to evaluate individual and overall effects of PFAS on GH and longitudinal BP measures during pregnancy. We included 826 pregnant women from the Jiashan Birth Cohort established between 2016 and 2018.

Association of pre-pregnancy body mass index and gestational weight gain with neonatal anogenital distance in a Chinese birth cohort.

Background: This study aimed to investigate the associations of pre-pregnancy body mass index (BMI) and gestational weight gain (GWG) with anogenital distance (AGD) among newborns.

Methods: The study included 556 mother-newborn pairs from the Jiashan birth cohort. AGD was measured as AGD (from the center of the anus to the anterior base of the penis, where the penile tissue meets the pubic bone) and AGD (from the center of the anus to the posterior base of the scrotum, where the skin changes from rugate to smooth) in males and AGD (from the center of the anus to the clitoris) and AGD (from the center of the anus to the posterior convergence of the fourchette) in females.

Discovery of -aryl sulphonamide-quinazoline derivatives as anti-gastric cancer agents and activating the Hippo signalling pathway.

Hippo signalling pathway plays a crucial role in tumorigenesis and cancer progression. In this work, we identified an , compound as an anti-gastric cancer agent, which exhibited potent antiproliferative ability with IC values of 0.36 μM (MGC-803 cells), 0.

Review of NEDDylation inhibition activity detection methods.

NEDDylation is a post-translational modification of a protein, which transfers Ubiquitin like protein NEDD8 (Neuronal Precursor Cell-expressed Developmentally Down-regulated Protein 8) to the lysine residue of the product through a three-stage enzymatic reaction, and widely regulates many biological processes, such as cell cycle signal transduction and immune recognition. In the past ten years, we have witnessed tremendous progress in the study of protein ubiquitination modification, from modification mechanisms to drug development. Which suggests that inhibition of NEDDylation is an effective way to inhibit tumor.

Prenatal plasma concentrations of Perfluoroalkyl and polyfluoroalkyl substances and neuropsychological development in children at four years of age.

Objective: Perfluoroalkyl and polyfluoroalkyl substances (PFASs) are persistent pollutants and have endocrine disruptive and neurotoxic effects. The association between maternal PFAS concentrations and neuropsychological development in children is inconclusive. The present study aimed to examine the effect of maternal PFAS concentrations on neuropsychological development in 4-years-old children.

Interactions between Nitrogen and Silicon in Rice and Their Effects on Resistance toward the Brown Planthopper .

Nitrogen (N) and silicon (Si) are two important nutritional elements required for plant growth, and both impact host plant resistance toward insect herbivores. The interaction between the two elements may therefore play a significant role in determining host plant resistance. We investigated this interaction in rice ( L.