JOURNAL OF MEDICINAL CHEMISTRY
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2025
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IF 6.8
Jianxia Zhang,Yi Wang,Mengying Wang,Peipei Wang,Hao Yan,Dalong Wang,Jiahao Zheng,Bin Li,Chaoyue Chen,Di Cao,Xiaohui Zheng,Xiaokun Li,Kun Wang,Zhiguo Liu
Fibroblast growth factor receptors (FGFRs) play a critical role in the regulation of cancer cell proliferation, differentiation, and migration. However, the development of acquired resistance to FGFR inhibitors remains a major challenge in treating non-small cell lung cancer (NSCLC), particularly due to mutations at the gatekeeper residue. In this study, we report the discovery of a series of irreversible FGFR inhibitors targeting gatekeeper mutations in FGFR1–3, utilizing a 2,4,5-trisubstituted pyrimidine scaffold. Through rational design, structure–activity relationship optimization, and pharmacokinetic evaluation, compound ng 12l emerged as a promising candidate. It demonstrated potent inhibition of FGFR1–3 gatekeeper mutations in vitro along with favorable pharmacokinetic properties. The efficacy of 12l in targeting FGFR1 gatekeeper mutations was confirmed in assays using L6-FGFR1V561M/F cells. Furthermore, in xenograft models using both H1581 and L6-FGFR1V561M cells, 12l exhibited robust anti-tumor activity with minimal toxicity. These findings position 12l as a promising therapeutic agent for overcoming gatekeeper-mediated resistance in NSCLC.
研究领域:
肿瘤学
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药物化学
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药理学
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癌症生物学
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PubMed
高影响因子
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
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2021
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IF 3.935
Qinghua Weng,Wei Tan,Ren-yue Yu,Ren-ai Xu,Yu Chen
Pemigatinib is an oral, selective, potent, competitive inhibitor acting on fibroblast growth factor receptor (FGFR)1, FGFR2, and FGFR3, which has obtained accelerated approval in the USA through a test approved by the USA FDA. It is not only significant in the therapy of adult recurrent, unresectable, metastatic or locally advanced cholangiocarcinoma, but also plays an important role in treating adult patients with FGFR2 fusion or other rearrangements. The aim of our research was to establish and verify a reliable and quick ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) assay to determine the level of pemigatinib in rat plasma. The analyte was prepared using a simple and convenient approach with acetonitrile for protein crash, and then separated from the matrix on a Waters Acquity UPLC BEH C18 column (2.1 mm × 50 mm, 1.7 μm) in a gradient elution program, where the mobile phase was consisted of acetonitrile and 0.1 % formic acid in water and was set at 0.40 mL/min flow rate. Selective reaction monitoring (SRM) was used to conducted for UPLC-MS/MS dectection with ion transitions at m / z 488.01 → 400.98 for pemigatinib and m / z 447.00 → 361.94 for erdafitinib (Internal standard, IS), respectively. This method had good linearity in a 0.5−1000 ng/mL calibration range for pemigatinib, where the lower limit of quantification (LLOQ) was validated at 0.5 ng/mL. The precision of pemigatinib for intra- and inter-day was less than 13.3 %, and the accuracy was determined to be from −4.8%–11.2%. During the assay in plasma samples, the analyte was found to be stable. Besides, matrix effect and recovery of the analyte and IS were acceptable. The novel optimized UPLC-MS/MS assay was also suitable for determining the concentration level of pemigatinib in a pharmacokinetic study after a single dose of 1.35 mg/kg pemigatinib orally to the rats.
研究领域:
药物分析
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生物化学
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医学研究
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DOI
高影响因子
Pharmaceutics
·
2026
·Vol. 18
·期 7
·869
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IF 6.9
Jiangtao Zhou,Yuhui Ge,Ran Li,Zhuoyang Cheng,Jianping Gao,Bin Zheng
Background: Skin photoaging, primarily induced by chronic ultraviolet (UV) radiation exposure, is characterized by dryness, wrinkle formation, pigmentation abnormalities, and reduced skin elasticity, resulting from oxidative stress, inflammation, and degradation of the extracellular matrix. Codonopsis pilosula , a traditional food–medicine homologous plant, is recognized for its anti-aging properties. However, its lipophilic components (designated as CP-L) remain insufficiently explored. Methods: Herein, we developed a thermosensitive nanogel encapsulating CP-L-loaded transferosomes (CP-L nanogel) to enhance topical delivery and evaluated its effects in both a UV-induced photoaging mouse model and UVB-irradiated HaCaT keratinocytes. Results: In UV-induced mice, topical application of the nanogel markedly reduced skin wrinkling and epidermal hyperplasia, with epidermal thickness decreased by 83.2% compared to the model group ( p < 0.01), and restored skin elasticity and collagen deposition, as evidenced by a 35.5% increase in collagen area fraction ( p < 0.01). Correspondingly, in UVB-irradiated HaCaT cells, it significantly increased cell viability from 53.0 ± 9.6% to 89.4 ± 1.0% ( p < 0.01) and suppressed apoptosis from 30.1 ± 0.48% to 12.4 ± 0.66% ( p < 0.01). Furthermore, the CP-L nanogel consistently attenuated oxidative stress, with SOD, CAT, and GSH-Px activities increased by 73.1%, 188.1%, and 18.2%, respectively ( p < 0.01), and MDA levels reduced by 71.0% ( p < 0.01), while inflammatory responses were suppressed, as TNF-α, IL-1α, IL-1β, and IL-6 levels decreased by 28.3%, 22.6%, 12.8% and 31.9%, respectively ( p < 0.01). Mechanistically, transcriptomic and molecular analyses revealed that the nanogel potently inhibited the UV-induced activation of the FGFR/PI3K/AKT/mTOR/p70S6K signaling cascade at both transcriptional and protein levels, with the phosphorylation levels of FGFR, PI3K, AKT, mTOR, and p70S6K significantly reduced by 43.9%, 30.9%, 38.8%, 34.9%, and 57.3%, respectively ( p < 0.01). Molecular docking and dynamics simulations identified isofuranodienone and aromadendrene oxide-(2) as key constituents with high-affinity, stable binding to FGFR1 and AKT1. The cytoprotective effect of the nanogel was completely abolished by co-treatment with the FGFR inhibitor PD173074 , confirming functional reliance on this pathway. Enhanced cellular delivery of the formulation was directly demonstrated by flow cytometry, showing an approximately 1.8-fold increase in cellular uptake compared to the free drug ( p < 0.01). Conclusions: Collectively, these results demonstrated that the CP-L nanogel alleviated skin photoaging through a multi-faceted mechanism involving enhanced cellular delivery, potent antioxidant and anti-inflammatory activities, and specific inhibition of the FGFR/PI3K/AKT/mTOR signaling cascade, highlighting its potential as a multitargeted topical agent derived from an edible plant.
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PubMed
高影响因子
Nature Communications
·
2019
·Vol. 10
·期 1
·1-15
·
IF 11.878
Jin Nan,Bi Aiwei,Lan Xiaojing,Xu Jun,Wang Xiaomin,Liu Yingluo,Wang Ting,Tang Shuai,Zeng Hanlin,Chen Ziqi,Tan Minjia,Ai Jing,Xie Hua,Zhang Tao,Liu Dandan,Huang Ruimin,Song Yue,Leung Elaine Lai-Han,Yao Xiaojun,Ding Jian,Geng Meiyu,Lin Shu-Hai,Huang Min
One of the biggest hurdles for the development of metabolism-targeted therapies is to identify the responsive tumor subsets. However, the metabolic vulnerabilities for most human cancers remain unclear. Establishing the link between metabolic signatures and the oncogenic alterations of receptor tyrosine kinases (RTK), the most well-defined cancer genotypes, may precisely direct metabolic intervention to a broad patient population. By integrating metabolomics and transcriptomics, we herein show that oncogenic RTK activation causes distinct metabolic preference. Specifically, EGFR activation branches glycolysis to the serine synthesis for nucleotide biosynthesis and redox homeostasis, whereas FGFR activation recycles lactate to fuel oxidative phosphorylation for energy generation. Genetic alterations of EGFR and FGFR stratify the responsive tumors to pharmacological inhibitors that target serine synthesis and lactate fluxes, respectively. Together, this study provides the molecular link between cancer genotypes and metabolic dependency, providing basis for patient stratification in metabolism-targeted therapies.
研究领域:
肿瘤学
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代谢组学
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转录组学
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癌症生物学
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药理学
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高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2024
·
IF 5.7
Liuying Zhu,Minghui Wang,Hongyan Li,Ting Luo,Zeyuan Deng,Jing Li,Liufeng Zheng,Bing Zhang
3′-Sialyllactose (3′-SL), a major acidic oligosaccharide found in human milk, has been investigated to improve cognitive-enhancing effects with 3 weeks old C57BL/6 mice by administering 3′-SL orally at a dose of 350 mg/kg/day for 6 weeks. Behavioral tests indicated that supplementation with 3′-SL promoted cognitive and memory development in young mice. Through interaction network and coenrichment analysis, nine differentially expressed genes (DEGs) related to memory and cognition were identified and localized in the hippocampal tissue of mice. The intervention of 3′-SL significantly increased the metabolism of sialic acid in mouse hippocampal tissue and promoted the expression of learning-related genes (p < 0.05). Notably, it increased the expression of genes associated with neural cell adhesion molecule (NCAM, p < 0.05), glutamate receptors, and fibroblast growth factor receptor (FGFR, p < 0.05). This suggests that 3′-SL may elevate polysialylated NCAM (PSA-NCAM) levels, which could subsequently interact with FGFR and glutamate receptors, thereby enhancing synaptic growth and plasticity. Additionally, 3′-SL altered the composition of the mouse intestinal microbiota. The synergistic action of gut microbiota and intestinal sialidase promoted the production of free sialic acid, providing essential nutritional elements for the development of the brain’s nervous system. In conclusion, our findings provide new insights into the promoting effect of 3′-SL on cognitive development in growing mice and elucidate its molecular mechanisms.
研究领域:
神经科学
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分子生物学
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营养科学
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微生物学
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PubMed
高影响因子
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