Drug Development Research最新文献

{"title":"Disruption of the FOXM1 Regulatory Region Inhibits Tumor Progression in Ovarian Cancer by CRISPR-Cas9","authors":"Yujie Chen,&nbsp;Yingzhuo Xue,&nbsp;Qiuwen Jiang,&nbsp;Yunfeng Jin,&nbsp;Weiguan Chen,&nbsp;Minhui Hua","doi":"10.1002/ddr.70049","DOIUrl":"10.1002/ddr.70049","url":null,"abstract":"<div>\u0000 \u0000 <p>Ovarian cancer is the seventh most common lethal tumor among women in the world. FOXM1 is a transcription factor implicated in the initiation and progression of ovarian cancer by regulating key oncogenic genes. The role of regulatory regions in regulating the expression of FOXM1 in ovarian cancer is not completely clarified. Treatment with bromodomain and extraterminal (BET) inhibitors JQ-1 and I-BET were explored in ovarian cancer cell lines (OVCAR3, A2780, or SKOV3) to evaluate FOXM1 expression and biological behavior by qPCR, CCK8 assay, colony formation assay, wound-healing, and transwell assays. The regulatory regions (enhancer sequence spanning promoter or exon 1) of FOXM1 were deleted using CRISPR-Cas9 in the OVCAR3 cell line. FOXM1 expression and tumor biological behavior were further assessed in FOXM1 regulatory regions deleted OVCAR3 cell line. The mouse xenograft model was assessed at the indicated time points following subcutaneous injection of enhancer-deleted cells. Treatment with the JQ-1 and I-BET reduced the expression of FOXM1, decreasing cell proliferation, migration, and invasion in a panel of ovarian cancer cell lines including OVCAR3, A2780, and SKOV3 cells. By mining the published ChIP-sequencing data (H3K27Ac) from 12 ovarian cancer cell lines, we identified a potential enhancer and promoter region. Deletion of the spanning enhancer and promoter region of FOXM1 reduced mRNA and protein expression. Similarly, cell proliferation, migration, invasion, and tumorigenesis in both cells and mouse xenograft models were significantly attenuated. Our study demonstrates that JQ-1 and I-BET can regulate the expression of the FOXM1 gene-relating network. These data also indicate that disruption of the span enhancer and promoter region activity of FOXM1 has a vital role in the anti-ovarian cancer effect, hiding a potential opportunity for the evaluation of this non-coding DNA deletion disrupts the FOXM1 transcriptional network in ovarian cancer development.</p>\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":"143002011","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}

{"title":"Downregulation of LncRNA CCAT1 Enhances Chemosensitivity in Cisplatin-Resistant Gastric Cancer Cells","authors":"Qiong Wu,&nbsp;Chenglou Zhu,&nbsp;Tiantian Zhao,&nbsp;Tianxiang Liu,&nbsp;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}

{"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,&nbsp;Ying Cai,&nbsp;Yixin Sun,&nbsp;Peiji Zeng,&nbsp;Wei Wang,&nbsp;Wenhui Wang,&nbsp;Xiaohua Jiang,&nbsp;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}

{"title":"Naringenin Inhibits Ferroptosis in Renal Tubular Epithelial Cells of Diabetic Nephropathy Through SIRT1/FOXO3a Signaling Pathway","authors":"Yi Zhou,&nbsp;Tianchi Hu,&nbsp;Huarong Zeng,&nbsp;Lin Lin,&nbsp;Huan Xie,&nbsp;Rong Lin,&nbsp;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 Fe²⁺, 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}

{"title":"Current Strategies and Future Dimensions in the Development of KRAS Inhibitors for Targeted Anticancer Therapy","authors":"Laura D'Alessio-Sands,&nbsp;Joshua Gaynier,&nbsp;Victoria Michel-Milian,&nbsp;Ayodeji A. Agbowuro,&nbsp;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}

{"title":"Bioinformatics Exploration of the Therapeutic Potential of Lotus Seed Compounds in Multiple Sclerosis: A Network Analysis of c-Jun Pathway","authors":"Rapuru Rushendran,&nbsp;Ankul Singh S.,&nbsp;Rukaiah Fatma Begum,&nbsp;Vellapandian Chitra,&nbsp;Nemat Ali,&nbsp;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}

{"title":"An Inducible Neural Stem Progenitor Cell Model for Testing Therapeutic Interventions Against Neurodegeneration FENIB","authors":"Alessandro Giustini,&nbsp;Alice Maiocchi,&nbsp;Ilaria Serangeli,&nbsp;Martina Pedrini,&nbsp;Anna Quintiliani,&nbsp;Valentina Sabato,&nbsp;Francesca Bonato,&nbsp;Pierfausto Seneci,&nbsp;Giuseppe Lupo,&nbsp;Daniele Passarella,&nbsp;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}

{"title":"Sulfamethizole Attenuates Pentylenetetrazole-Induced Seizures in Mice via mTOR Inhibition","authors":"Lazari Kambli,&nbsp;Dezaree Raut,&nbsp;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}

{"title":"Reduction-Responsive RGD-Docetaxel Conjugate: Synthesis, In Vitro Drug Release and In Vitro Antitumor Activity","authors":"Qingqing Li,&nbsp;Yufeng Liu,&nbsp;Yilin Cheng,&nbsp;Huaibao Cao,&nbsp;Kunda Du,&nbsp;Tianyu Zhu,&nbsp;Defeng Xu,&nbsp;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}

{"title":"Orthoallosteric EGFR-TKIs: A New Paradigm in NSCLC Treatment Strategy Targeting the C797S Mutation","authors":"Iqrar Ahmad,&nbsp;Harun M. Patel","doi":"10.1002/ddr.70036","DOIUrl":"10.1002/ddr.70036","url":null,"abstract":"<div>\u0000 \u0000 <p>The remarkable clinical success of third-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) has significantly advanced the treatment landscape for non-small-cell lung cancer (NSCLC). However, the emergence of the tertiary point mutation C797S poses a substantial obstacle to their clinical efficacy, leading to a dearth of FDA-approved targeted therapies for patients harboring this mutation. Addressing this pressing clinical challenge necessitates the development of novel therapeutic agents targeting the clinically challenging EGFR mutation. This review delves into the design strategies, antitumor activity, and crucial protein–drug interactions of recently introduced Orthoallosteric fourth-generation EGFR-TKIs. These inhibitors are distinguished by their ability to simultaneously engage both the canonical orthosteric (ATP) binding site and the allosteric site. By shedding light on these key aspects, the review serves as a valuable resource for medicinal chemists, empowering them to propel the advancement of fourth-generation EGFR inhibitors.</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":"142892963","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}