自引率: 17.2%
被引量: 40425
通过率: 暂无数据
审稿周期: 2.63
版面费用: 暂无数据
国人发稿量: 158
投稿须知/期刊简介:
The European Journal of Medicinal Chemistry publishes studies on all aspects of medicinal chemistry: Organic synthesis; Biological behavior; Pharmacological activity; Drug design; QSAR; Molecular Modeling; Drug-receptor interactions; Molecular aspects of drug metabolism; Prodrug synthesis and Drug targeting. The journal accepts papers from any country, European or otherwise, and provides a medium for publication of original papers, laboratory notes, short or preliminary communications, new products and invited reviews.
期刊描述简介:
The European Journal of Medicinal Chemistry publishes studies on all aspects of medicinal chemistry: Organic synthesis; Biological behavior; Pharmacological activity; Drug design; QSAR; Molecular Modeling; Drug-receptor interactions; Molecular aspects of drug metabolism; Prodrug synthesis and Drug targeting. The journal accepts papers from any country, European or otherwise, and provides a medium for publication of original papers, laboratory notes, short or preliminary communications, new products and invited reviews.
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Optimization of pyrazole/1,2,4-triazole as dual EGFR/COX-2 inhibitors: Design, synthesis, anticancer potential, apoptosis induction and cell cycle analysis.
A novel series of pyrazol-4-yl-1,2,4-triazole-3-thiol derivatives 14a-l was designed, prepared and characterized by many spectroscopic techniques. All the novel compounds were screened for their anti-proliferative activity towards breast cancer cell line (MCF-7), colon cancer cell line (HT-29) and lung cancer cell line (A-549) utilizing celecoxib, erlotinib and osimertinib as standards. Compounds 14b, 14g and 14k were the most active towards HT-29, MCF-7 and A-549 cell lines, sequentially with IC50 = 1.20-2.93 μM compared with celecoxib (IC50 = 16.47-41.45 μM), erlotinib (IC50 = 1.95-33.57 μM) and osimertinib (IC50 = 0.75-3.45 μM). These most active derivatives 14b, 14g and 14k were further investigated for their inhibitory potential against COX and EGFR enzymes. These compounds 14b, 14g and 14k suppressed COX-2 (IC50 = 0.560-4.692 μM), EGFRWT (IC50 = 0.121-0.423 μM) and EGFRT790M (IC50 = 0.076-0.764 μM) enzymes. Compounds 14b, 14g and 14k displayed apoptosis induction by up-regulating Bax and down-regulating Bcl-2 protein levels. Cell cycle analysis recorded that exposure of MFC-7 cells to compound 14g resulted in a significant increase in the percentage of cells at the G2/M to 39.15 % compared to the standard erlotinib (9.87 %). Docking study of the most potent candidates 14b, 14g and 14k within COX-2, EGFRWT and EGFRT790M active regions was conducted to suggest the binding mode of these compounds inside these target enzymes.
被引量：- 发表：1970
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Discovery and preclinical evaluations of drug candidate DA-0157 capable of overcoming EGFR drug-resistant mutation C797S and EGFR/ALK co-mutations.
Activating mutations in the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) are significant oncogenic drivers in non-small cell lung cancer (NSCLC) patients. Despite several approved EGFR and ALK inhibitors, drug-resistant mutations pose a major challenge. Especially, there is currently no approved EGFR inhibitors targeting the C797S mutation, a refractory mutation resistant to the third-generation EGFR inhibitors. Furthermore, an increasing number of patients with EGFR/ALK co-mutations have been identified in clinical practice, yet there are no effective therapeutic options available for them. In this study, we report the discovery and preclinical evaluations of a new small-molecule drug candidate, DA-0157, which is capable of overcoming EGFR drug-resistant mutation C797S and EGFR/ALK co-mutations. DA-0157 demonstrated excellent in vitro efficacy, significantly inhibiting various EGFRC797S mutants resistant to the third-generation EGFR inhibitors, ALK rearrangements, and EGFR/ALK co-mutations. In vivo studies revealed that DA-0157 substantially inhibited tumor growth in the LD1-0025-200717 EGFRDel19/T790M/C797S PDX model (40 mg/kg/d, TGI: 98.3 %), Ba/F3-EML-4-ALK-L1196 M CDX model (40 mg/kg/d, TGI: 125.2 %), and NCI-H1975 EGFRDel19/T790M/C797S & NCI-H3122 (EML4-ALK) dual-side implantation CDX model (40 mg/kg/d, TGI: 89.5 % & 113.9 %). DA-0157 demonstrates favorable pharmacokinetic properties and safety. Currently, DA-0157 (DAJH-1050766) is undergoing Phase I/II clinical trials.
被引量：- 发表：1970
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Synthesis and biological evaluation of novel pyrrolo[2,3-b]pyridine derivatives as potent GSK-3β inhibitors for treating Alzheimer's disease.
The development of potent glycogen synthase kinase-3β (GSK-3β) inhibitor has been increasingly recognized as the candidate treatment against the multifactorial pathogenic mechanism of Alzheimer's disease (AD). This study prepared various new pyrrolo[2,3-b]pyridine derivatives, evaluated the anti-AD activities and detected the security based on the structure-guided rational design. Our results indicated that many pyrrolo[2,3-b]pyridine derivatives had strong GSK-3β inhibitory activities, particularly compounds 41, 46 and 54, with the half maximal inhibitory concentrations (IC50) of 0.22, 0.26 and 0.24 nM, respectively, and each of them generally possessed GSK-3β selectivity over 24 structurally similar kinases. In addition, further targeting studies at the cellular level revealed that compound 41 increased GSK-3β phosphorylation at Ser9 site dose-dependently for inhibiting GSK-3β activity, therefore inhibiting the hyperphosphorylation of tau protein by decreasing the p-tau-Ser396 abundance. Moreover, 41 up-regulated β-catenin and neurogenesis-related markers (GAP43 and MAP-2), thereby promoting neurite outgrowth of neurons in SH-SY5Y cells. According to the in vitro cells assay, 41 showed the lower cytotoxicity to SH-SY5Y cells with a survival rate of over 70 % at the concentration of 100 μM. In vivo efficacy and acute toxicity experiments showed that, 41 effectively ameliorated the dyskinesia in AlCl3-induced zebrafish AD models and exhibited its low-toxicity nature in C57BL/6 mice. Overall, the pyrrolo[2,3-b]pyridine derivative 41 could serve as a promising GSK-3β inhibitor for treating AD.
被引量：- 发表：1970
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From challenges to solutions: A review of fourth-generation EGFR tyrosine kinase inhibitors to overcome the C797S triple mutation in non-small cell lung cancer.
This Review discusses recent advancements in the development of fourth-generation "Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors (EGFR-TKIs)" targeting resistance mutations, with an emphasis on the C797S mutation in "Non-small Cell Lung Cancer (NSCLC)". While first, second, and third-generation EGFR-TKIs have made significant progress in overcoming EGFR kinase resistance, the emergence of the EGFR-C797S mutation poses a substantial challenge, particularly in the context of resistance to Osimertinib. Fourth-generation TKIs are classified into ATP-competitive, allosteric, and ortho-allosteric inhibitors, with the goal of enhancing specificity for mutant EGFR while minimizing off-target effects on wild-type EGFR to reduce toxicity. This Review provides a detailed analysis of structural modifications and their impact on drug potency and selectivity, with the aim of improving efficacy against resistant NSCLC. Preclinical and early-phase clinical trials of these inhibitors are promising, though further optimization of pharmacokinetic and safety profiles is crucial for future clinical success. This work offers key insights for medicinal chemists in the design and development of fourth-generation EGFR inhibitors to address drug-resistant mutations in NSCLC.
被引量：- 发表：1970
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Catalytic Lysine745 targeting strategy in fourth-generation EGFR tyrosine kinase inhibitors to address C797S mutation resistance.
Overcoming resistance to third-generation tyrosine kinase inhibitors (TKIs) such as Osimertinib, particularly due to the emergence of the C797S mutation, remains a key challenge in non-small cell lung cancer (NSCLC) therapy. This review highlights recent advancements in the development of fourth-generation EGFR inhibitors that specifically target the catalytic Lys745 residue, aiming to overcome resistance associated with Osimertinib. Both covalent and non-covalent inhibitors targeting Lys745 were explored, using warheads like sulfonyl fluoride, phosphine oxides, esters, and trisubstituted imidazoles. Sulfonyl fluoride was particularly effective in forming covalent bonds with Lys745, while non-covalent analogues demonstrated flexibility with reduced off-target effects. The manuscript highlights the importance of warhead design, molecular docking, protein XRD study and structure-activity relationships (SAR) for optimizing Lys745-targeting inhibitors. The study suggests that hybrid scaffolds combining key pharmacophoric features from Osimertinib and Brigatinib along with Lys745 targeting warheads, could enhance selectivity and potency. Future efforts should focus on refining bioavailability, identifying new scaffolds by employing drug design strategies. Fourth-generation TKIs targeting Lys745 offer a novel therapeutic avenue, potentially overcoming mutation-induced resistance and improving NSCLC treatment outcomes. This approach represents a critical advancement toward durable clinical responses in patients with drug-resistant cancer.
被引量：- 发表：1970
