SPECTROCHIMICA ACTA PART A-MOLECULAR AND BIOMOLECULAR SPECTROSCOPY
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2023
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IF 4.4
Shao-Liang Jiang,Wan-Jun Wang,Zhe-Ying Hu,Rong-Juan Zhang,Jie-Hua Shi
The primary coverage of this paper is to investigate the molecular interaction of JAK2 inhibitor, fedratinib (FED) with BSA/HAG proteins through multispectral approaches and molecular docking as well as MD calculation. Arrival at a conclusion, the endogenous fluorescence of BSA/HAG protein was quenched separately in the form of static and mixed quenching. The FED-BSA and FED-HAG complexes with the stoichiometric ratio of 1:1 were formed in the interaction process. And, The K b values of these complexes were of 10 4 –10 5 M −1 and 10 5 –10 6 M −1 , respectively, representing that the FED-HAG complex exhibited a comparatively high affinity compared to the FED-BSA complex. It is confimed that FED inserted into the interface area between subdomain IIA and IIB of BSA (marked as site II') and the bucket-shaped hydrophobic cavity of HAG, respectively, resulting in the slight alteration in the secondary structure of BSA/HAG and the micro-environment round Tyr and Trp residues. The expetimental results also confirmed that van der Waals forces (VDW), hydrogen bonds and hydrophobic interaction played a dominant role in the formation of two stable complexes. The above experimental results were supplemented and verified through molecular docking and MD simulation. Meanwhile, the effects of common ions on affinity were explored. This study could shine a light on evaluating the pharmacological properties of the JAK inhibitor FED, understanding the distribution and operation of the drug in the body, and leading to the development of the creation of novel medication devise.
研究领域:
药理学
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生物化学
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计算生物学
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DOI
PubMed
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
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2026
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IF 5.2
Zhen Wang,Xin Lv,Hang Yin,Lili Jiang,Yuntao Ji,Xing Zhang,Changqing Qv,Yong Liu
Fedratinib is the second drug approved by the FDA for adult patients with myelofibrosis (MF) following ruxolitinib; however, the mechanism of its dose-limiting toxicity, particularly hepatotoxicity, remains poorly unclear. Given that inhibition of UDP-glucuronosyltransferases (UGTs) is a key predictor of drug-induced liver injury, this research investigates the inhibition of fedratinib on UGTs and human liver microsomes (HLMs), and evaluates the associated risks of adverse drug reactions. Our screening revealed that fedratinib potently inhibit UGT1A1, UGT1A3, and UGT2B15. Enzyme kinetic analyses further indicated that fedratinib exhibited competitive inhibition for UGT1A1-mediated 4-methylumbelliferone (4-MU) glucuronidation ( K i,u = 0.39 ± 0.03 μM), and UGT1A3-mediated 4-MU glucuronidation ( K i,u = 0.61 ± 0.18 μM). In HLMs, it exhibited mixed inhibition of SN-38 glucuronidation ( K i,u = 0.58 ± 0.13 μM) and non-competitive inhibition of chenodeoxycholic acid glucuronidation ( K i,u = 2.38 ± 0.17 μM). The results of risk assessment indicated that clinically relevant doses of fedratinib could significantly increase the area under curve (AUC) of drugs mainly metabolized by UGT1A1 and UGT1A3, suggesting a potential risk of clinically significant drug-drug interactions (DDIs). The current research provides useful information for the possible hepatotoxicity mechanism and clinical safe medication of fedratinib.
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PubMed
高影响因子
Frontiers in Pharmacology
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2018
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IF 3.831
Chen Donglai,Zhang Fuquan,Wang Jinhui,He Hua,Duan Shanzhou,Zhu Rongying,Chen Chang,Yin Lichen,Chen Yongbing
Background: Erlotinib (ELTN)-based targeted therapy as first-line treatment for epidermal growth factor receptor (EGFR)-mutant lung cancers suffers from insufficient selectivity, side effects, and drug resistance, which poses critical challenges in the clinical setting. Acquired resistance of ELTN results in extremely poor prognoses of non-small cell lung cancer (NSCLC) patients, wherein activation of the JAK2/STAT3 signaling pathway has been proven to induce acquired ELTN resistance.Methods: In this study, we developed a nanoparticle (NP) delivery system based on Food and Drug Administration (FDA)-approved poly(ethylene glycol) (PEG)-poly(lactic acid) (PLA) for the co-delivery of ELTN and fedratinib (FDTN, a small-molecular, highly selective JAK2 inhibitor). Both ELTN and FDTN could be encapsulated into the PEG-PLA NPs via optimization of the encapsulation method. The effect of NPs on NSCLC cells was evaluated by MTT assay. Western blotting was performed to study the molecular mechanisms of NPs inhibiting the downstream pathways of EGFR in vitro. The histological analysis and protein expression in vivo were assessed by hematoxylin/eosin (H&E) staining and immunohistochemistry, respectively.Results: The drug cargoes exhibited great stability, and could be released more efficiently in the acidic tumorous condition. Mechanistic study showed that FDTN notably down-regulated the expression levels of proteins in the JAK2/STAT3 signaling pathway, including p-EGFR, p-JAK2, p-STAT3 and Survivin, therefore reversing the ELTN resistance. As a result, synergistic anti-cancer effect was achieved by PEG-PLA NPs encapsulating both ELTN and FDTN in ELTN-resistant NSCLC tumors both in vitro and in vivo, and lower systemic side effect was noted for the co-delivery NPs compared to free drugs.Conclusion: This study provides a promising approach to overcome the ELTN resistance in the treatment of NSCLC, and the use of FDA-approved materials with clinically applied/investigated chemical drugs may facilitate the translation of the current delivery system.
研究领域:
药学
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肿瘤学
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纳米技术
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分子生物学
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癌症研究
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产品关联
DOI
PubMed
高影响因子
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