Drug Development Research最新文献_第5页

Downregulation of LncRNA CCAT1 Enhances Chemosensitivity in Cisplatin-Resistant Gastric Cancer Cells LncRNA CCAT1的下调增强顺铂耐药胃癌细胞的化疗敏感性

IF 3.5 4区医学

Drug Development Research Pub Date : 2025-01-20 DOI: 10.1002/ddr.70048

Qiong Wu, Chenglou Zhu, Tiantian Zhao, Tianxiang Liu, Mingxu Da

{"title":"Downregulation of LncRNA CCAT1 Enhances Chemosensitivity in Cisplatin-Resistant Gastric Cancer Cells","authors":"Qiong Wu, Chenglou Zhu, Tiantian Zhao, Tianxiang Liu, Mingxu Da","doi":"10.1002/ddr.70048","DOIUrl":"10.1002/ddr.70048","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 <p>Chemotherapy is an effective treatment for gastric cancer. However, many patients develop resistance to chemotherapeutic agents during clinical treatment. LncRNA CCAT1 has recently been shown to influence cellular resistance to specific chemotherapeutic drugs, but its role in gastric cancer remains underexplored. This study aims to investigate the role of LncRNA CCAT1 in cisplatin resistance in gastric cancer cells and its potential underlying mechanisms. Gastric cancer cell lines with acquired resistance were established. The expression of CCAT1 was assessed in both cisplatin-sensitive and cisplatin-resistant AGS cell lines. CCAT1 expression was knocked down in AGS/DDP cells, and the changes in IC50 values were measured using the Cell Counting Kit-8 (CCK-8) assay. Apoptosis in gastric cancer cells was evaluated by flow cytometry. Additionally, Western blotting was employed to measure the expression levels of PI3K/AKT/mTOR signaling pathway proteins and apoptosis-related proteins in both interference and control groups. RT-qPCR results indicated that CCAT1 expression was significantly elevated in cisplatin-resistant gastric cancer cells compared to non-resistant cells. Similarly, CCK-8 assay results demonstrated that knocking down CCAT1 in resistant cells increased their sensitivity to cisplatin treatment. Flow cytometry and Western blot results further confirmed that silencing CCAT1 promoted apoptosis in these cells. Additionally, the expression of PI3K/AKT/mTOR signaling pathway proteins was higher in resistant cells compared to their sensitive counterparts, and silencing CCAT1 in AGS/DDP cells resulted in reduced expression of these proteins. In conclusion, the above studies demonstrated that LncRNA CCAT1 induced cisplatin resistance in gastric cancer cells.</p>\u0000 </section>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 1","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143002015","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A Real-World Disproportionality Analysis of Histamine H2-Receptors Antagonists (Famotidine): A Pharmacovigilance Study Based on Spontaneous Reports in the FDA Adverse Event Reporting System 组胺h2受体拮抗剂（法莫替丁）的实际歧化分析：一项基于FDA不良事件报告系统中自发报告的药物警戒研究。

IF 3.5 4区医学

Drug Development Research Pub Date : 2025-01-16 DOI: 10.1002/ddr.70045

Dongdong Zhang, Ying Cai, Yixin Sun, Peiji Zeng, Wei Wang, Wenhui Wang, Xiaohua Jiang, Yifan Lian

{"title":"A Real-World Disproportionality Analysis of Histamine H2-Receptors Antagonists (Famotidine): A Pharmacovigilance Study Based on Spontaneous Reports in the FDA Adverse Event Reporting System","authors":"Dongdong Zhang, Ying Cai, Yixin Sun, Peiji Zeng, Wei Wang, Wenhui Wang, Xiaohua Jiang, Yifan Lian","doi":"10.1002/ddr.70045","DOIUrl":"10.1002/ddr.70045","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 <p>Famotidine is an H2 receptor antagonist and is currently used on a large scale in gastroenterology. However, Famotidine may also cause severe toxicity to organ systems, including the blood system, digestive system, and urinary system. The objective of this study was to scientifically and systematically investigate the adverse events (AEs) of Famotidine in the real world through the FDA Adverse Event Reporting System (FAERS) database. A disproportionality analysis was used to quantify the signals of AEs associated with Famotidine in FAERS data from the first quarter of 2004 to the first quarter of 2023. The clinical features, onset time, oral and intravenous administration and severe consequences of Famotidine induced AEs were further analyzed. Among the four tests, we found several AEs that were not mentioned in the drug label. For example, abdominal pain upper, abdominal discomfort, dyspepsia, liver disorder, gastrooesophageal reflux disease, and rhabdomyolysis. These AEs are consistent with the drug instructions. Interestingly, we found several unreported AEs, such as: cerebral infarction, hypocalcaemia, hallucination, visual, hypomagnesaemia, hypoparathyroidism, diabetes insipidus, vulvovaginal candidiasis, retro-orbital neoplasm, neuroblastoma recurrent, and malignant cranial nerve neoplasm. Most of our findings are consistent with clinical observations and drug labels, and we also found possible new and unexpected AEs signals, which suggest the need for prospective clinical studies to confirm these results and explain their relationships. Our findings provide valuable evidence for further safety studies.</p>\u0000 </section>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 1","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001990","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Naringenin Inhibits Ferroptosis in Renal Tubular Epithelial Cells of Diabetic Nephropathy Through SIRT1/FOXO3a Signaling Pathway 柚皮素通过SIRT1/FOXO3a信号通路抑制糖尿病肾病肾小管上皮细胞铁下垂

IF 3.5 4区医学

Drug Development Research Pub Date : 2025-01-12 DOI: 10.1002/ddr.70044

Yi Zhou, Tianchi Hu, Huarong Zeng, Lin Lin, Huan Xie, Rong Lin, Mengya Huang

{"title":"Naringenin Inhibits Ferroptosis in Renal Tubular Epithelial Cells of Diabetic Nephropathy Through SIRT1/FOXO3a Signaling Pathway","authors":"Yi Zhou, Tianchi Hu, Huarong Zeng, Lin Lin, Huan Xie, Rong Lin, Mengya Huang","doi":"10.1002/ddr.70044","DOIUrl":"10.1002/ddr.70044","url":null,"abstract":"<div>\u0000 \u0000 <p>Naringenin has the potential to regulate ferroptosis and mitigate renal damage in diabetic nephropathy (DN). However, it remains unclear whether the naringenin's effects in DN are linked to its ability to regulate ferroptosis. This study investigated the potential anti-ferroptosis properties of naringenin in high glucose (HG)-induced renal tubular epithelial cell models. HK-2 cells were cultured in HG medium to establish the DN cell model. HK-2 cells were treated with different doses of naringenin to explore the effect of naringenin. The CCK-8 results show that 50 μM ~ 200 μM of naringenin do not affect the viability of HK-2 cells and the viability of HG-induced HK-2 cells increase in a dose-dependent manner with naringenin treatment. Additionally, naringenin increased the levels of IL-10 while decreasing the levels of IL-1β, TNF-α, IL-6, and ROS in HG-induced HK-2 cells. Naringenin also reduced the levels of Fe<sup>2+</sup>, oxidized lipid ROS, MDA, 4-HNE, ACSL4, and TFR1 in HG-induced HK-2 cells, while increasing the levels of non-oxidized lipid ROS, SOD, GSH-Px, SLC7A11, and GPX4. Meanwhile, naringenin restored the levels of MMP, ATP and MPTP opening, reduced OCR in HG-induced HK-2 cells. Furthermore, naringenin reversed the decreased expression of SIRT1, p-FOXO3a, Nrf2 and Nuclear Nrf2 caused by HG. SIRT1 inhibitor EX527 and Nrf2 inhibitor ML385 attenuated the effects of naringenin on ferroptosis in HG-induced HK-2 cells, with EX527 demonstrating a stronger reversal effect on ferroptosis than ML385. These results suggest that naringenin inhibits ferroptosis in HG-induced HK-2 cells mainly through SIRT1/FOXO3a signaling pathway. This finding further enhanced our understanding of the mechanism behind naringenin's protective effect on DN.</p></div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 1","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142970008","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Current Strategies and Future Dimensions in the Development of KRAS Inhibitors for Targeted Anticancer Therapy KRAS抑制剂靶向抗癌治疗的当前策略和未来发展方向。

IF 3.5 4区医学

Drug Development Research Pub Date : 2025-01-12 DOI: 10.1002/ddr.70042

Laura D'Alessio-Sands, Joshua Gaynier, Victoria Michel-Milian, Ayodeji A. Agbowuro, Christopher M. Brackett

{"title":"Current Strategies and Future Dimensions in the Development of KRAS Inhibitors for Targeted Anticancer Therapy","authors":"Laura D'Alessio-Sands, Joshua Gaynier, Victoria Michel-Milian, Ayodeji A. Agbowuro, Christopher M. Brackett","doi":"10.1002/ddr.70042","DOIUrl":"10.1002/ddr.70042","url":null,"abstract":"<div>\u0000 \u0000 <p>KRAS is a proto-oncogene that is found to be mutated in 15% of all metastatic cancers with high prevalence in pancreatic, lung, and colorectal cancers. Additionally, patients harboring KRAS mutations respond poorly to standard cancer therapy. As a result, KRAS is seen as an attractive target for targeted anticancer therapy. Over the last decade, this protein has evolved from being termed “undruggable” to producing two clinically approved drugs along with several more in clinical development, and many under preclinical investigations. This review details the development of various KRAS-targeted molecules with emphasis on the different drug design strategies employed by examining the following areas: (1) Direct inhibition of KRAS mutants using small molecule binders, (2) Inhibiting the activated state of KRAS mutants using a binary complex of small molecule binders and cyclophilin A, and (3) Targeted degradation of KRAS mutants using the PROTAC approach. We assess the pharmacological attributes and possible clinical benefits of the different molecules and look to the next frontiers in the application of KRAS inhibitors as anticancer agents.</p></div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 1","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142970006","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Bioinformatics Exploration of the Therapeutic Potential of Lotus Seed Compounds in Multiple Sclerosis: A Network Analysis of c-Jun Pathway 莲子化合物治疗多发性硬化症潜力的生物信息学探索：c-Jun通路的网络分析。

IF 3.5 4区医学

Drug Development Research Pub Date : 2025-01-05 DOI: 10.1002/ddr.70038

Rapuru Rushendran, Ankul Singh S., Rukaiah Fatma Begum, Vellapandian Chitra, Nemat Ali, Bhupendra G. Prajapati

{"title":"Bioinformatics Exploration of the Therapeutic Potential of Lotus Seed Compounds in Multiple Sclerosis: A Network Analysis of c-Jun Pathway","authors":"Rapuru Rushendran, Ankul Singh S., Rukaiah Fatma Begum, Vellapandian Chitra, Nemat Ali, Bhupendra G. Prajapati","doi":"10.1002/ddr.70038","DOIUrl":"10.1002/ddr.70038","url":null,"abstract":"<div>\u0000 \u0000 <p>The central nervous system is affected by multiple sclerosis (MS), a chronic autoimmune illness characterized by axonal destruction, demyelination, and inflammation. This article summarizes the state of the field, highlighting its complexity and significant influence on people's quality of life. The research employs a network pharmacological approach, integrating systems biology, bioinformatics, and pharmacology to identify biomarkers associated with MS. Utilizing <i>Nelumbo Nucifera</i> (Lotus) seeds, the study involves toxicity assessments, biomolecule screening, and target prediction. Advanced computational methodologies are employed, including molecular docking and dynamic simulations, to assess potential therapeutic interactions. Biomolecule screening identifies eight active compounds from Lotus seeds, including Anonaine and Liriodenine. Target prediction reveals 264 common targets with MS-related genes. Protein-protein interaction analysis establishes a complex network, identifying central targets like SRC and AKT1. Bioinformatics enrichment analysis uncovers potential therapeutic candidates and pathways. A Biomolecule-Target-Pathway network diagram visualizes interactions, with Anonaine and Liriodenine exhibiting strong binding affinities in molecular docking studies. Molecular dynamics simulations provide insights into dynamic interactions. In conclusion, through advanced computational techniques, it unveils molecular interactions, potential therapies, and pathways, bridging predictions with practical applications. Anonaine and Liriodenine show promise in curbing MS biomarkers.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 1","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142930862","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

An Inducible Neural Stem Progenitor Cell Model for Testing Therapeutic Interventions Against Neurodegeneration FENIB 用于测试神经退行性变性治疗干预FENIB的可诱导神经干祖细胞模型。

IF 3.5 4区医学

Drug Development Research Pub Date : 2025-01-03 DOI: 10.1002/ddr.70041

Alessandro Giustini, Alice Maiocchi, Ilaria Serangeli, Martina Pedrini, Anna Quintiliani, Valentina Sabato, Francesca Bonato, Pierfausto Seneci, Giuseppe Lupo, Daniele Passarella, Elena Miranda

{"title":"An Inducible Neural Stem Progenitor Cell Model for Testing Therapeutic Interventions Against Neurodegeneration FENIB","authors":"Alessandro Giustini, Alice Maiocchi, Ilaria Serangeli, Martina Pedrini, Anna Quintiliani, Valentina Sabato, Francesca Bonato, Pierfausto Seneci, Giuseppe Lupo, Daniele Passarella, Elena Miranda","doi":"10.1002/ddr.70041","DOIUrl":"10.1002/ddr.70041","url":null,"abstract":"<p>Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is a neurodegenerative pathology caused by accumulation of mutant neuroserpin (NS) polymers inside the endoplasmic reticulum (ER) of neurons, leading to cellular toxicity and neuronal death. To date, there is no cure for FENIB, and only palliative care is available for FENIB patients, underlining the urgency to develop therapeutic strategies. The purpose of this work was to create a cellular system designed for testing small molecules able to reduce the formation of NS polymers. Our results show the generation and characterisation of a novel cell culture model for FENIB based on neural stem progenitor cells (NPCs) with inducible expression of either wild type (WT) or G392E NS, a variant that causes severe FENIB. We also report the use of these novel cell lines to explore the effects of four different proteolysis targeting chimaera (PROTAC) compounds, small bivalent molecules engineered to bind to the E3 ubiquitin ligase cereblon, and to NS through a recruiting motif based on the small molecule embelin. This approach aims to enhance the degradation of mutant NS after retro-translocation to the cytosol by facilitating its targeting to the proteasome. Our results show little toxicity and no variation in NS levels with any of the compounds tested. In conclusion, this work sets the basis for future attempts to identify molecules able to prevent NS accumulation inside the ER of cultured cells.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 1","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11696822/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Sulfamethizole Attenuates Pentylenetetrazole-Induced Seizures in Mice via mTOR Inhibition 磺胺甲唑通过抑制mTOR减轻戊四唑诱导的小鼠癫痫发作。

IF 3.5 4区医学

Drug Development Research Pub Date : 2024-12-26 DOI: 10.1002/ddr.70039

Lazari Kambli, Dezaree Raut, Lokesh Kumar Bhatt

{"title":"Sulfamethizole Attenuates Pentylenetetrazole-Induced Seizures in Mice via mTOR Inhibition","authors":"Lazari Kambli, Dezaree Raut, Lokesh Kumar Bhatt","doi":"10.1002/ddr.70039","DOIUrl":"10.1002/ddr.70039","url":null,"abstract":"<div>\u0000 \u0000 <p>Epilepsy affects at least 1% of the global population of all socioeconomic backgrounds. Data obtained from previous studies suggest the role of mTOR signaling in epileptogenesis. The present study aimed to investigate the hypothesis that mTOR inhibitor sulfamethizole might produce antiepileptic effects in pentylenetetrazole (PTZ)-induced kindling seizures in mice. For induction of kindling, mice were administered 40 mg/kg PTZ on alternate days for 13 days. The severity of kindling was analyzed using a seizure intensity score. Rotarod performance, actophotometer, and chimney tests were performed to check muscle coordination and locomotor functions. mTOR and IL-6 levels were measured in the brain homogenate. Histological analyses were done using hematoxylin–eosin and cresyl violet stains. Sulfamethizole was administered daily at 10 and 50 mg/kg doses. PTZ administration resulted in kindling seizures in the PTZ-veh group. In addition, mice from the PTZ-veh group showed decreased fall time in rotarod performance, reduced locomotor activity, and failed chimney tests. mTOR and IL-6 levels were also increased in the brain, along with neuronal degeneration and a decreased layer of neuronal cells in the hippocampus. Treatment with sulfamethizole at 50 mg/kg significantly ameliorated seizure intensity score, seizure latency and duration, muscle coordination, and locomotor functions compared to the PTZ-veh group. It also downregulated brain mTOR and IL-6 expression significantly. In conclusion, sulfamethizole showed antiepileptic activity against PTZ-induced kindling seizure in mice via mTOR inhibition.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 1","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892965","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Reduction-Responsive RGD-Docetaxel Conjugate: Synthesis, In Vitro Drug Release and In Vitro Antitumor Activity 还原反应性rgd -多西紫杉醇缀合物：合成、体外药物释放和体外抗肿瘤活性。

IF 3.5 4区医学

Drug Development Research Pub Date : 2024-12-25 DOI: 10.1002/ddr.70043

Qingqing Li, Yufeng Liu, Yilin Cheng, Huaibao Cao, Kunda Du, Tianyu Zhu, Defeng Xu, Hang Hu

{"title":"Reduction-Responsive RGD-Docetaxel Conjugate: Synthesis, In Vitro Drug Release and In Vitro Antitumor Activity","authors":"Qingqing Li, Yufeng Liu, Yilin Cheng, Huaibao Cao, Kunda Du, Tianyu Zhu, Defeng Xu, Hang Hu","doi":"10.1002/ddr.70043","DOIUrl":"10.1002/ddr.70043","url":null,"abstract":"<div>\u0000 \u0000 <p>Poor selectivity to tumor cells is a major drawback in the clinical application of the antitumor drug docetaxel (DTX). Peptide–drug conjugates (PDCs) constructed by modifying antitumor drugs with peptide ligands that have high affinity to certain overexpressed receptors in tumor cells are increasingly assessed for their possibility of tumor-selective drug delivery. In the present research, DTX is condensed with 3-(pyridin-2-yldisulfanyl) propanoic acid via ester bond to obtain the intermediate Py-SS-DTX. Two conjugates GSS-DTX and RGDC-SS-DTX were obtained by conjugation of Py-SS-DTX with glutathione (GSH) and RGDC peptide through a thiol-disulfide exchange reaction. Afterwards, these two peptide–DTX conjugates were characterized by proton nuclear magnetic resonance, Fourier transform infrared spectroscopy, and high-resolution mass spectrometry. The GSS-DTX and RGDC-SS-DTX were further evaluated in terms of drug release, cell cycle inhibition, cell apoptosis, and cytotoxicity. The results show that both the GSS-DTX and RGDC-SS-DTX exhibit reduction-responsive drug release and RGDC-SS-DTX exhibit higher reduction-responsiveness. The in vitro antitumor activity study shows that RGDC-SS-DTX exhibits enhanced G2/M phase arrest, cell apoptosis rate, and cytotoxicity as compared to GSS-DTX and free DTX. Besides, RGDC-SS-DTX shows reduced cytotoxicity on normal cells as compared to free DTX. The RGDC-SS-DTX synthesized in this study represents a novel DTX conjugate to effectively and selectively inhibit tumor cells.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 1","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Orthoallosteric EGFR-TKIs: A New Paradigm in NSCLC Treatment Strategy Targeting the C797S Mutation 正变构EGFR-TKIs：靶向C797S突变的非小细胞肺癌治疗策略的新范式

IF 3.5 4区医学

Drug Development Research Pub Date : 2024-12-25 DOI: 10.1002/ddr.70036

Iqrar Ahmad, Harun M. Patel

引用次数: 0

Design, Synthesis, Biological Evaluation and Molecular Docking Study of New 1,3,4-Thiadiazole-Based Compounds as EGFR Inhibitors 新型1,3,4-噻二唑类EGFR抑制剂的设计、合成、生物学评价及分子对接研究

IF 3.5 4区医学

Drug Development Research Pub Date : 2024-12-24 DOI: 10.1002/ddr.70035

Marwa I. Serag, Samar S. Tawfik, Hassan M. Eisa, Sahar M. I. Badr

{"title":"Design, Synthesis, Biological Evaluation and Molecular Docking Study of New 1,3,4-Thiadiazole-Based Compounds as EGFR Inhibitors","authors":"Marwa I. Serag, Samar S. Tawfik, Hassan M. Eisa, Sahar M. I. Badr","doi":"10.1002/ddr.70035","DOIUrl":"10.1002/ddr.70035","url":null,"abstract":"<div>\u0000 \u0000 <p>Five series of new 1,3,4-thiadiazole hybrids were designed and synthesized as promising EGFR inhibitors. Three human cancer cell lines were employed for testing each hybrid's in vitro antiproliferative efficacy; colon HCT-116, liver HepG-2 and breast MCF-7 using MTT assay. Comparing compound <b>9a</b> to the reference doxorubicin, <b>9a</b> shown superior activity to that of Dox with respect to MCF-7 (IC<sub>50</sub> 3.31 µM) while being secure for normal cells WI-38 (IC<sub>50</sub> = 43.99 µM). Further evaluation of the EGFR inhibitory activity of the most active candidates—<b>4a, 6b</b>, <b>8b, 9a</b>, and <b>9 d</b>—was performed. Of them, compounds <b>9a</b> and <b>8b</b> demonstrated the highest IC<sub>50</sub> values, 0.08 and 0.15 µM, respectively, relative to the reference gefitinib (IC<sub>50</sub> = 0.04 µM). Subsequent mechanistic analysis of compound <b>9a</b> revealed a notable 14.24-fold increase in overall apoptosis and a 28.92% cell cycle arrest at G2/M. Additionally, research on apoptosis demonstrated that it triggered the mitochondrial apoptotic pathway. In MCF-7 cells, it also led to an increase in ROS buildup. For the most powerful EGFR inhibitors, <b>9a</b> and <b>8b</b>, a molecular docking research was conducted, and all of the findings agreed with the biological findings.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 1","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881619","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0