JOURNAL OF CHEMICAL RESEARCH
·
2015
·
IF 0.633
Haidong Liu,Yuan Li,Dongdong Wang,Yu Qin,Min Ji
A convenient route for the synthesis of Novartis's second-generation anaplastic lymphoma kinase inhibitor Ceritinib (LDK378) involving starting materials that are commercially available has been achieved. The procedure employed mild reaction conditions and avoided the use of expensive reagents compared to the original synthetic route reported by Novartis. More importantly, gram scale synthesis was accomplished and this protocol could be valid in drug discovery synthesis.
研究领域:
药物化学
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有机合成
·
肿瘤学
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DOI
高影响因子
CHEMICAL RESEARCH IN TOXICOLOGY
·
2026
·
IF 4.1
Hang Yin,Xiaoyu Wang,Zhe Wang,Zhen Wang,Xin Lv,Lili Jiang,Jun Cao,Yong Liu
Anaplastic lymphoma kinase (ALK) inhibitors have shown remarkable efficacy in targeted therapy for non-small cell lung cancer (NSCLC). However, it is worth noting that they may cause clinical drug–drug interactions (DDIs) by inhibiting the activities of drug-metabolizing enzymes, thereby leading to unnecessary side effects. This study sought primarily to characterize the inhibition effects of four well-known ALK inhibitors, crizotinib, ceritinib, alectinib, and brigatinib, on human UDP-glucuronosyltransferases (UGTs) in vitro and to assess their potential DDI risks in vivo. Initial studies demonstrated that all tested ALK inhibitors exhibited a varying extent of inhibition profile on UGTs at starting test concentrations (100 or 60 μM). Subsequent kinetic experiments indicated that alectinib was a selective potent inhibitor for UGT1A4 in a competitive manner with a Ki,u value of 0.07 μM. Ceritinib exhibited a potent noncompetitive inhibition against UGT1A1 and UGT1A7 with Ki,u values of 1.28 and 3.08 μM, respectively, and a competitive inhibition against UGT2B7 with Ki,u of 1.16 μM. Crizotinib and brigatinib demonstrated potent inhibition against UGT2B7 and UGT1A8, respectively. In vitro–in vivo extrapolation (IVIVE) suggested that all four ALK inhibitors have potential for DDIs due to their inhibitory effects on UGTs. Among them, the DDI risks of alectinib and brigatinib were much higher than the FDA standard, which may have an impact on the safety of clinical drug use.
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产品关联
DOI
PubMed
高影响因子
LANGMUIR
·
2025
·
IF 3.9
Bolin Yue,Tingli Wang,Mengke Zhang,Xiaoyu Wu,Xu Xu,Zequan Li,Bohan Ye,Lei Liu,Shiyong Song
Proteolysis-targeting chimeric (PROTAC) technology represents a groundbreaking approach with immense potential for treating a wide range of diseases. However, its clinical application is often limited by challenges in solubility and permeability. Herein, we have developed an innovative three-in-one nanoparticulate therapeutic agent tailored for non-small-cell lung cancer (NSCLC). This agent features a PROTAC molecule derived from ceritinib, designated as 27B, serving as a targeted degrader of anaplastic lymphoma kinase (ALK). 27B is self-assembled with vitamin A palmitate (VAP) and vitamin E poly(ethylene glycol) succinate (TPGS) to form stable nanoparticles (BVT-NPs) that exhibit a uniform spherical morphology, excellent storage stability, and robust plasma stability. With an average particle size of approximately 130 nm and a loading capacity of 27B of 20%, BVT-NPs demonstrate a pH-responsive drug release profile. In vitro studies reveal that BVT-NPs significantly inhibit the proliferation of H3122 cells more effectively than free 27B, indicating a synergistic antitumor effect. Western blot analysis further confirms the superior efficacy of BVT-NPs in downregulating ALK and P-glycoprotein and upregulating Caspase-3. BVT-NPs markedly suppress tumor growth without inducing significant tissue toxicity. This carrier-free, multifunctional nanoparticulate system integrates PROTAC-mediated protein degradation with chemotherapy, thereby improving the PROTAC absorption and generating a synergistic therapeutic effect against NSCLC.
研究领域:
癌症治疗
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纳米医学
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药理学
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生物化学
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药物递送
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产品关联
DOI
PubMed
高影响因子
Scientific Reports
·
2016
·Vol. 6
·期 1
·1-9
·
IF 5.228
Gao Ningning,Zhong Jingjing,Wang Xiaodong,Jin Zhenchao,Li Wang,Liu Yu,Diao Yuwen,Wang Zhulin,Jiang Wenqi,Jin Guangyi
As new treatment approaches, both immunotherapy and targeted treatments have been used in the clinical treatment of cancers. These therapies are different from traditional surgery, chemotherapy and radiotherapy. Use of a combination of immunotherapy and targeted treatments may improve tumor clearance. We investigated the feasibility of combining tyrosine kinase inhibitors (TKIs, targeted drugs) and SZU-101 (a novel TLR7 agonist synthesized by our laboratory). Thirteen different TKIs were combined with or without SZU-101 and studied to determine their effects on immunocytes. On the basis of the distinctive results, lapatinib and sunitinib were selected for further tumor-inhibition investigation and determination of the underlying mechanism. Interestingly, we found lapatinib to work better with SZU-101, enhancing tumor clearance in vivo , without affecting the TLR7-NF-κB pathway activated by the TLR7 agonist in mouse spleen lymphocytes and bone marrow dendritic cells (BMDCs).
研究领域:
肿瘤学
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免疫学
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药理学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF SEPARATION SCIENCE
·
2021
·Vol. 44
·期 21
·3914-3923
·
IF 3.645
Zhao-Yang Wang,Hai-Long Wu,Yue-Yue Chang,Tong Wang,Wei Chen,Gao-Yan Tong,Ru-Qin Yu
An intelligent chemometric second-order calibration method called alternating trilinear decomposition- assisted multivariate curve resolution combined with high-performance liquid chromatography–diode array detection was used for the simultaneous quantification of nine tyrosine kinase inhibitors in three complex biological systems. The method allows simultaneous quantification of the components in different biological matrices without the need for cumbersome pre-treatment steps, complex elution conditions, and complete peak separation. Even with the varying time shift, severe peak overlap, and various unknown interferences, the proposed method can extract pure chromatographic and spectroscopic information for each analyte, while providing accurate qualitative and quantitative results of nine common tyrosine kinase inhibitors in three different biological matrices. All the drugs were eluted in 7 min. The results showed that the nine drugs in each matrix showed good linearity ( r > 0.984) in the calibration range with a root mean square error of calibration less than 0.9 μg/mL. The average spiked recoveries of the target analytes were all in the range of 83.4–110.0%, with standard deviations less than 9.0%. Finally, the classical method was used to validate the proposed method. In comparison to the traditional method, the proposed strategy is accuracy, simultaneous, and interference-free.
研究领域:
分析化学
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药物分析
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生物医学
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）