Investigational New Drugs最新文献_第4页

Discovery of potent CRBN-recruiting epidermal growth factor receptor (EGFR) degraders in vitro. 体外发现有效的crbn招募表皮生长因子受体（EGFR）降解物。

IF 2.7 3区医学

Investigational New Drugs Pub Date : 2025-06-01 Epub Date: 2025-04-29 DOI: 10.1007/s10637-025-01539-2

Wenbo Hu, Jinmei He, Tianyu Xie, Mengjia Zhou, Mingxia Liu, Xin Wang

{"title":"Discovery of potent CRBN-recruiting epidermal growth factor receptor (EGFR) degraders in vitro.","authors":"Wenbo Hu, Jinmei He, Tianyu Xie, Mengjia Zhou, Mingxia Liu, Xin Wang","doi":"10.1007/s10637-025-01539-2","DOIUrl":"10.1007/s10637-025-01539-2","url":null,"abstract":"Epidermal Growth Factor Receptor (EGFR), a transmembrane receptor tyrosine kinase (RTK) belonging to the ErbB family, initiates cancer-promoting pathways upon binding with epidermal growth factor (EGF). This activation leads to increased cellular proliferation, inhibition of apoptosis, invasion, and neovascularization. EGFR plays a critical role in non-small cell lung cancer (NSCLC) and is targeted by EGFR tyrosine kinase inhibitors (TKIs). However, resistance to these inhibitors often develops over time, complicating treatment strategies. Proteolysis-targeting chimeras (PROTACs) represent a novel class of drugs that induce targeted protein degradation by promoting ubiquitination upon binding, resulting in degradation via the 26S proteasome. This innovative strategy potentially addresses the drug resistance associated with small molecule inhibitors and holds promise for the treatment of NSCLC. In this paper, we designed and synthesized a series of small molecule PROTACs targeting EGFR utilizing WZ4002, known for its mutation selectivity, as the warhead. These compounds were evaluated for their antiproliferative activity against A549 and NCl-H1975 cell lines, with WZ4002 serving as a control drug. Most compounds exhibited moderate to strong activity against NCl-H1975 cells, with comparatively weaker effects on A549 cells. Among the tested compounds, HJM- 17 and HJM- 19 emerged as the most potent against NCl-H1975 cells. Further analysis through protein immunoblotting revealed that HJM- 17 effectively reduced the expression of EGFRL858R/T790M. These active compounds lay the groundwork for future studies focused on EGFR-targeting PROTACs.","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"560-581"},"PeriodicalIF":2.7,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144004969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Clinical features, treatment, and outcomes of anti-PD-L1 induced psoriasis. 抗pd - l1诱导的银屑病的临床特征、治疗和结局。

IF 2.7 3区医学

Investigational New Drugs Pub Date : 2025-06-01 Epub Date: 2025-06-06 DOI: 10.1007/s10637-025-01554-3

Jian Xiao, Zhi Xia, Zhu Wu, Min Fang

{"title":"Clinical features, treatment, and outcomes of anti-PD-L1 induced psoriasis.","authors":"Jian Xiao, Zhi Xia, Zhu Wu, Min Fang","doi":"10.1007/s10637-025-01554-3","DOIUrl":"10.1007/s10637-025-01554-3","url":null,"abstract":"Background: This study focuses on rare immune-mediated psoriasis induced by anti-PD-L1 drugs. Given that its clinical features have not been fully defined, the aim is to clarify the clinical manifestations, treatment, and outcomes of anti-PD-L1-induced psoriasis.Methods: We performed a retrospective analysis of psoriasis cases induced by anti-PD-L1 agents. The study involved systematically retrieving case reports from relevant databases up to April 23, 2025, for comprehensive evaluation.Results: This study included 31 patients, with 90.2% being male and a median age of 65 years (40-81 years). The anti-PD-L1 agents administered to patients included atezolizumab, durvalumab, and avelumab. Notably, 16 patients (51.6%) developed de novo psoriasis. The median time to psoriasis onset after drug initiation was 54.5 days (7-690 days), with plaque psoriasis being the most common clinical type (54.8%). In terms of treatment strategies, 19 patients (61.3%) discontinued anti-PD-L1 therapy, while 8 patients (25.8%) continued treatment. Following clinical interventions, including primarily the administration of topical steroids, symptomatic improvement or complete remission was reported in 25 patients (80.6%).Conclusion: When administering anti-PD-L1 agents, close monitoring for the onset of psoriatic symptoms in patients is essential to ensure timely detection and diagnosis. For patients who have been diagnosed with psoriasis, appropriate measures should be taken based on their specific clinical conditions, such as discontinuing anti-PD-L1 therapy or administering psoriasis treatment medications.","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"719-727"},"PeriodicalIF":2.7,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144234082","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Approval of high-benefit oncology drugs in Japan: utilization of expedited regulatory pathways for the accelerated approved anticancer drugs. 日本高效益肿瘤药物的批准：加速批准抗癌药物的加速监管途径的利用。

IF 2.7 3区医学

Investigational New Drugs Pub Date : 2025-06-01 Epub Date: 2025-06-04 DOI: 10.1007/s10637-025-01549-0

Ayumi Taguchi, Naoki Matsumaru, Katsura Tsukamoto

{"title":"Approval of high-benefit oncology drugs in Japan: utilization of expedited regulatory pathways for the accelerated approved anticancer drugs.","authors":"Ayumi Taguchi, Naoki Matsumaru, Katsura Tsukamoto","doi":"10.1007/s10637-025-01549-0","DOIUrl":"10.1007/s10637-025-01549-0","url":null,"abstract":"Early access to promising new drugs with superior efficacy compared to existing treatments is globally sought after. To facilitate such access, regulatory authorities in each country have implemented special regulatory measures that expedite drug approval. This study examined the approval lag of anticancer drugs granted accelerated approval (AA) by the U.S. Food and Drug Administration (FDA) and their corresponding approval timelines in Japan. Additionally, we assessed the use of expedited regulatory pathways in Japan. Our analysis included 55 anticancer drugs that received AA from the FDA between 2012 and 2021 and evaluated their approval in Japan through 2022. The median approval lag was 649 days, primarily attributable to submission delays. Drugs for which Japan participated in the pivotal FDA study and the use of expedited regulatory pathways in Japan had significantly shorter approval lags (P < 0.001 and P = 0.0172, respectively). However, the utilization of the recently implemented conditional early approval system was limited. Although AA anticancer drugs are often approved based on early clinical trial data, our findings highlight that participation in pivotal studies is crucial for minimizing approval delays in Japan. Despite improvements in drug approval timelines, substantial delays persist, underscoring the need for more effective utilization of expedited regulatory pathways. Enhancing collaboration in early-stage clinical trials and optimizing regulatory processes may facilitate faster access to high-benefit anticancer therapies in Japan.","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"701-708"},"PeriodicalIF":2.7,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144215814","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Navigating antibody‒drug conjugates (ADCs): from metastatic to early breast cancer treatment strategies. 导航抗体-药物偶联物（adc）：从转移到早期乳腺癌治疗策略。

IF 2.7 3区医学

Investigational New Drugs Pub Date : 2025-06-01 Epub Date: 2025-04-30 DOI: 10.1007/s10637-025-01525-8

Tala Najdi, Lea Awad, Antoine Chartouni, Charbel Soueidy, Hampig Kourie

{"title":"Navigating antibody‒drug conjugates (ADCs): from metastatic to early breast cancer treatment strategies.","authors":"Tala Najdi, Lea Awad, Antoine Chartouni, Charbel Soueidy, Hampig Kourie","doi":"10.1007/s10637-025-01525-8","DOIUrl":"10.1007/s10637-025-01525-8","url":null,"abstract":"We are currently living in the era of precision medicine, and antibody‒drug conjugates (ADCs) represent promising advancements in targeted cancer therapy. While several ADCs have been investigated over the years, only three have gained FDA approval for breast cancer (BC): ado-trastuzumab emtansine (T-DM1/Kadcyla), trastuzumab deruxtecan (T-DXd/Enhertu), and sacituzumab govitecan (SG/Trodelvy). This review focuses on the three approved ADCs for BC, reviewing the trials that led to their approval and detailing the ongoing trials testing their clinical efficacy and safety profiles. We examine ongoing trials targeting both metastatic and early-stage patients. Notably, we explore trials incorporating investigational ADCs into early management strategies, addressing the unique challenges of biomarker identification, target toxicity, and cost-effectiveness. By summarizing the current landscape of FDA-approved and investigational ADCs, this study highlights the evolving nature of BC treatment. Preliminary findings from ongoing trials suggest that early integration of ADCs can lead to significant improvements in disease-free survival, reinforcing their role in personalized medicine. As research advances, ADCs are likely to become a cornerstone of breast cancer treatment, providing new hope for better patient outcomes.","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"466-503"},"PeriodicalIF":2.7,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12310797/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143965042","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Retrospective analysis of clinical features of pembrolizumab induced psoriasis. 派姆单抗致银屑病临床特点回顾性分析。

IF 2.7 3区医学

Investigational New Drugs Pub Date : 2025-06-01 Epub Date: 2025-04-30 DOI: 10.1007/s10637-025-01536-5

Ming Shu, Zhiqiang Fan, Bin Huang, Chunjiang Wang

{"title":"Retrospective analysis of clinical features of pembrolizumab induced psoriasis.","authors":"Ming Shu, Zhiqiang Fan, Bin Huang, Chunjiang Wang","doi":"10.1007/s10637-025-01536-5","DOIUrl":"10.1007/s10637-025-01536-5","url":null,"abstract":"To explore the clinical features of pembrolizumab induced psoriasis to provide reference for the optimal treatment of immune checkpoint inhibitor-induced psoriasis. Clinical reports of pembrolizumab induced psoriasis were collected by searching the database until January 31, 2025. The clinical data extracted from the collected articles were retrospectively analyzed. A total of 42 patients were included, 76.2% male, with a median age of 69 years (range 28, 83). These patients included 21 (50.0%) patients with new-onset psoriasis and 21 (50.0%) patients with pre-existing psoriasis. The duration of onset of psoriasis was 8 weeks (range 0.4, 108), and the duration of onset of new psoriasis was longer than that of preexisting psoriasis (9 weeks vs. 7.2 weeks). Plaque psoriasis (38.1%) and psoriatis vulgaris (33.3%) were the most commonly reported phenotypes. After discontinuation or continuation of medication, 90.5% of patients experienced partial or complete improvement of skin symptoms after receiving topical, biologics, and oral systemic treatments. Pembrolizumab induced psoriasis can lead to various types of psoriasis, mainly in elderly and male patients. The pathogenesis and optimal treatment of Pembrolizumab in psoriasis require further investigation.","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"582-587"},"PeriodicalIF":2.7,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144010075","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

The recombinant anti-MET/EpCAM bispecific antibody fragment: a promising novel therapeutic approach for breast cancer treatment. 重组抗met /EpCAM双特异性抗体片段：一种有前景的乳腺癌治疗新方法。

IF 2.7 3区医学

Investigational New Drugs Pub Date : 2025-06-01 Epub Date: 2025-05-30 DOI: 10.1007/s10637-025-01546-3

Roya Mirzaei, Mohammadreza Azimi, Soroush Karimi, Mahshid Seyed Karimi, Seyed Ali Mir Aghel, Malihe Salehi, Neda Jalili, Fatemeh Yadegari, Leila Farahmand

{"title":"The recombinant anti-MET/EpCAM bispecific antibody fragment: a promising novel therapeutic approach for breast cancer treatment.","authors":"Roya Mirzaei, Mohammadreza Azimi, Soroush Karimi, Mahshid Seyed Karimi, Seyed Ali Mir Aghel, Malihe Salehi, Neda Jalili, Fatemeh Yadegari, Leila Farahmand","doi":"10.1007/s10637-025-01546-3","DOIUrl":"10.1007/s10637-025-01546-3","url":null,"abstract":"Our study aims to target Met and EpCAM to inhibit angiogenesis in breast cancer, particularly triple-negative breast cancer (TNBC). We have developed a new bispecific antibody that targets both MET and EpCAM, which are commonly overexpressed in tumor cells. This antibody aims to reduce tumor cell proliferation and spread. After cloning and expressing the anti-Met/EPCAM sequence in Escherichia coli, we confirmed its accuracy through Western blot analysis. Flow cytometry indicated its binding activities to MET and EPCAM on MDA-MB-231 and MCF-7 cell lines. Our antibody showed anti-proliferative potential as indicated by apoptosis and MTT assay, leading to the inhibition of migration and invasion in breast cancer cell lines. After conducting a thorough analysis of cytokine production, we discovered that our bispecific antibody effectively influenced the levels of IL-8 and IL-6. These cytokines play crucial roles in angiogenesis and the progression of breast cancer. These findings indicate that our bispecific antibody holds promise as a potential therapy for triple-negative breast cancer. It has the potential to impede the formation of new blood vessels in tumors, thus restraining their growth and spread.","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"687-700"},"PeriodicalIF":2.7,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144186992","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Understanding the differentiation syndrome in acute promyelocytic leukemia: a comprehensive updated review. 了解急性早幼粒细胞白血病的辨证：一项全面的最新综述。

IF 2.7 3区医学

Investigational New Drugs Pub Date : 2025-06-01 Epub Date: 2025-06-25 DOI: 10.1007/s10637-025-01556-1

Nahed Damaj, Nadim Elias, Toufic Zeidan, Joseph Kattan

{"title":"Understanding the differentiation syndrome in acute promyelocytic leukemia: a comprehensive updated review.","authors":"Nahed Damaj, Nadim Elias, Toufic Zeidan, Joseph Kattan","doi":"10.1007/s10637-025-01556-1","DOIUrl":"10.1007/s10637-025-01556-1","url":null,"abstract":"The concept of differentiation therapy emerged from the fact that hormones or cytokines may promote differentiation ex vivo, thereby irreversibly changing the phenotype of cancer cells. Its hallmark success has been the treatment of acute promyelocytic leukemia (APL), a condition that is now highly curable by the combination of retinoic acid (RA) and arsenic. Differentiation syndrome (DS) is a common and potentially life-threatening condition that was initially described with the induction therapy of targeted agents in acute promyelocytic leukemia (APL). DS is typically marked by symptoms such as fever, difficulty breathing, low blood pressure, weight gain, fluid buildup in the pleural or pericardial cavities, and acute kidney failure. The incidence of DS in APL patients varies from 2 to 27% reflecting the discrepancies in diagnostic criteria, in various treatment protocols, and sometimes the use of preventive treatments. Corticosteroids, with or without cytoreductive therapy, should be initiated immediately upon suspicion of DS to mitigate related morbidity and mortality. In cases of severe DS, targeted anti-leukemic therapy should be halted. This review will cover the pathogenesis of DS, its clinical presentations, diagnostic criteria, management approaches, and the importance of implementing prospective tracking in clinical trials.","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"750-756"},"PeriodicalIF":2.7,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144484299","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Clinical characterizations, management, and prognosis in immune checkpoint inhibitor-induced myelitis. 免疫检查点抑制剂诱导的脊髓炎的临床特征、管理和预后。

IF 2.7 3区医学

Investigational New Drugs Pub Date : 2025-06-01 Epub Date: 2025-06-09 DOI: 10.1007/s10637-025-01553-4

Yi-Xiao Li, Rui-Yun Wang, Zhi-Hang Lu, Wei-Cong Zhang, Yong-Jian Wang, Ming Meng, Yan-Lei Hao

{"title":"Clinical characterizations, management, and prognosis in immune checkpoint inhibitor-induced myelitis.","authors":"Yi-Xiao Li, Rui-Yun Wang, Zhi-Hang Lu, Wei-Cong Zhang, Yong-Jian Wang, Ming Meng, Yan-Lei Hao","doi":"10.1007/s10637-025-01553-4","DOIUrl":"10.1007/s10637-025-01553-4","url":null,"abstract":"The expanding clinical application of immune checkpoint inhibitors (ICIs) has led to increasing recognition of neurological immune-related adverse events, among which myelitis represents a rare but clinically significant complication. Currently, most available data come from case reports or small case series, highlighting the need for comprehensive characterization. Our study systematically analyzed the clinical features of ICI-induced myelitis to improve diagnostic and therapeutic approaches. Through a comprehensive literature review up to February 28, 2025, we identified and analyzed 36 cases of ICI-associated myelitis from 27 publications. The study cohort had a median age of 58 years (range 16-81) with male predominance (58.3%). Clinical presentations included isolated myelitis (63.9%) and multifocal neurological involvement (36.1%), most commonly manifesting meningoencephalomyelitis/encephalomyelitis. The median time to symptom onset was 2 months (range 0.3-8) after treatment initiation, with a median of 4 treatment cycles (range 1-51). The most frequently associated malignancies were melanoma and lung cancer, with programmed cell death protein-1 inhibitor being the most commonly used regimen (69.4%). Diagnostic evaluation revealed longitudinally extensive spinal cord lesions (≥ 3 vertebral segments) in 75.0% of patients, along with frequent inflammatory cerebrospinal fluid abnormalities. Neural autoantibodies were detected in 33.3% of cases. Treatment strategies predominantly involved corticosteroids (97.2%) and ICI discontinuation (91.7%). While most patients (72.2%) showed improvement, relapses occurred in 30.6% of cases. These findings emphasize the importance of early recognition and prompt immunosuppressive therapy for ICI-induced myelitis.","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"742-749"},"PeriodicalIF":2.7,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144258064","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Unraveling BOLD-100 synergistic potential in pleural mesothelioma treatment: an in vitro study. 揭示BOLD-100在胸膜间皮瘤治疗中的协同潜力：一项体外研究。

IF 2.7 3区医学

Investigational New Drugs Pub Date : 2025-06-01 Epub Date: 2025-05-08 DOI: 10.1007/s10637-025-01540-9

Gregorio Bonsignore, Elia Ranzato, Simona Martinotti

引用次数: 0

Research progress on cancer-related epigenetic switches. 癌症相关表观遗传开关的研究进展。

IF 2.7 3区医学

Investigational New Drugs Pub Date : 2025-06-01 Epub Date: 2025-06-13 DOI: 10.1007/s10637-025-01555-2

Chunyu Yu, Jie Sun, Jinlong Tong, Ziqing Xu, Qijia Zhang

引用次数: 0