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
·
有机合成
·
肿瘤学
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DOI
高影响因子
TOXICOLOGY
·
2025
·
IF 4.6
Shiyi Tan,Yun Yang,Li Ma,Xulei Zuo,Jianhua Rao,Yuepu Pu,Feng Cheng,Zhongze Gu,Juan Zhang
Ceritinib, a next-generation anaplastic lymphoma kinase inhibitor used to treat non-small cell lung cancer, has been increasingly associated with drug-induced liver injury (DILI), especially in the context of drug–drug interactions (DDIs). To elucidate the hepatotoxic risk of ceritinib in combination therapies, we conducted a real-world pharmacovigilance analysis of the FDA Adverse Event Reporting System (FAERS) and experimentally validated the results using human liver organoids. Disproportionality analysis revealed that ceritinib administered in combination therapy was more likely to induce DILI than its monotherapy, with the strongest correlation observed for ceritinib combined with ibuprofen (reporting odds ratio [ROR] = 12.01). Ibuprofen and acetaminophen (a classic DILI-associated drug with an ROR of 5.82) were selected for further combination studies using the liver organoid model. Both ceritinib–ibuprofen and ceritinib–acetaminophen combinations exhibited synergistic hepatotoxicity in organoids, with ceritinib–ibuprofen demonstrating a more pronounced effect, as demonstrated by the Bliss independence model based on organoid cell viability data. Mechanistically, ibuprofen possibly exacerbates ceritinib-induced hepatotoxicity by suppressing CYP3A4 activity, thereby impairing ceritinib metabolic clearance and enhancing its hepatotoxicity. Together, these findings provide a multidimensional understanding of DILI risks associated with ceritinib combination therapies. By integrating pharmacovigilance signals with physiologically relevant in vitro validation, this study highlights the utility of the human liver organoids for elucidating the mechanisms of hepatotoxicity insights and supporting safer prescribing practices, especially when ceritinib is co-administered with non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen in real-world clinical settings.
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产品关联
DOI
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
·
2026
·
IF 10.4
Jiang Feng,Fu Huang-xi,Wang Lan,Pan Ze-zheng,Jiang Yan-qi,Liu Ning,Chen Xue-qin,Gao Zi-zheng,Wu Wen-tong,Yan Hao,Yang Xiao-chun,Yang Bo,He Qiao-jun,Luo Pei-hua,Xu Zhi-fei
Ceritinib, an anaplastic lymphoma kinase (ALK) inhibitor, is associated with cardiovascular adverse events, yet the mechanisms remain incompletely understood. Here, we show that ceritinib impairs left ventricular systolic function in mice and induces cardiomyocyte apoptosis, and identify AKT (Ser473) suppression as a key initiating event. Loss of AKT activity is paralleled by reduced phosphorylation of mTOR (Ser2448) and ULK1 (Ser757), consistent with enhanced autophagy initiation. Concurrently, loss of inhibitory GSK3β (Ser9) phosphorylation correlates with impaired lysosomal function, reflected by disrupted cathepsin D maturation and reduced lysosomal acidification. This mismatch between enhanced autophagy initiation and impaired lysosomal clearance impairs autophagic flux despite preserved autophagosome-lysosome fusion, and causes mitochondrial damage, evidenced by reduced TOMM20 and HSP60 expression and membrane potential loss. Transcriptomic and functional analyses identify AKT2 as a particularly vulnerable isoform in this network. Metformin co-treatment preserves cardiac function and attenuates apoptosis. Mechanistically, metformin increases AMPK (Thr172) phosphorylation and reduces TFEB (Ser122) phosphorylation, restores CTSD maturation, and decreases LC3-II accumulation. These protective effects occur without reversing the suppressed AKT (Ser473) or GSK3β (Ser9) phosphorylation. Together, these findings establish that AKT suppression drives ceritinib cardiotoxicity through autophagic flux impairment and mitochondrial injury, and position AMPK-driven, TFEB-associated lysosomal restoration as a mechanism-based cardioprotective strategy independent of AKT recovery.
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DOI
高影响因子
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
·
2025
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IF 4.7
Zhen-Peng Yu,Ke-Xin Sun,Dan Zhang,Zhi-Qiang Yu,Deng-Yun Chen,Hong Zhu,Hongwei Si,Peng-Fei Dai
Anaplastic lymphoma kinase (ALK) is prominently expressed in numerous malignant tumors, which lead to aberrant tumor proliferation, invasion and metastasis. Ceritinib (LDK378), as second-generation targeted drugs, has been used to treat advanced ALK-positive non-small cell lung cancer (NSCLC). Herein, we sought to develop a novel ALK-positron emission tomography/magnetic resonance (PET/MR) tracer 68 Ga-DOTA-CTB ( 68 Ga labeled ceritinib) based on ceritinib scaffold to monitor the ALK expression levels during targeted therapy with ceritinib. The 68 Ga-DOTA-CTB radiotracer, obtained via a simple labeling procedure, exhibits favorable radiochemical purity, stability, and pharmacokinetic properties. Subsequently, cellular uptake experiments have demonstrated that 68 Ga-DOTA-CTB could be accumulated in H2228 cells. Imaging and biodistribution experiments have revealed significant uptake of the radiotracer in the tumors of the experimental group, while tumors in the blocking group, which were saturated with an excess of precursor, exhibited a markedly reduced level of radioactivity. These empirical findings suggest that 68 Ga-DOTA-CTB holds substantial potential as a novel PET/MR imaging tracer for ALK-positive tumors.
研究领域:
肿瘤学
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核医学
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分子影像学
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产品关联
DOI
PubMed
高影响因子
AMB Express
·
2022
·Vol. 12
·期 1
·1-15
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IF 4.126
Liu Shasha,She Pengfei,Li Zehao,Li Yimin,Yang Yifan,Li Linhui,Zhou Linying,Wu Yong
According to a 2019 report from the Centers of Disease Control and Prevention (CDC), methicillin-resistant Staphylococcus aureus (MRSA) was listed as one of the “serious threats” that had become a global public challenge in hospitals and community. Biofilm-associated infections and refractory persisters of S. aureus also impede the effectiveness of conventional antibiotics that have greatly increased difficulty in clinical therapy. There is an urgent need to develop new antimicrobials with antibiofilm and anti-persister capacities, and drug repurposing is the most effective and most economical solution to the problem. The present study profiles the antimicrobial activity of ceritinib, a tyrosine kinase inhibitor, against S. aureus in vitro and in vivo. We investigated the antimicrobial efficacy of ceritinib against planktonic and persistent S. aureus by a time-killing kinetics assay. Then, antibiofilm effect of ceritinib was assessed by crystal violet staining and laser confocal microscope observation. Ceritinib showed biofilm inhibition and mature biofilm eradication, and possesses robust bactericidal activity against S. aureus persisters. We also evaluated antimicrobial efficacy in vivo using a subcutaneous abscess infection model. Ceritinib ameliorated infection in a subcutaneous abscess mouse model and only showed negligible systemic toxicity in vivo. Mechanism exploration was conducted by transmission electron microscopy, fluorescently labeled giant unilamellar vesicle assays, and a series of fluorescent dyes. In conclusion, we find ceritinib represents potential bactericidal activity against MRSA by disrupting cell membrane integrity and inducing reactive oxygen species production, suggesting ceritinib has the potential to treat MRSA-related infections.
研究领域:
微生物学
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药理学
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传染病
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药物再利用
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DOI
PubMed
高影响因子
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