Drugs in Research & Development最新文献

{"title":"The Influence of Renal or Hepatic Impairment on the Pharmacokinetics of Iclepertin (BI 425809): Results from Two Phase I Open-Label, Non-randomised, Single Dose, Parallel Design Studies.","authors":"HeeJae Choi, Shilpa Madari, Elmar Daalman, Brett A English, Atef Halabi, Kathrin Hohl, Yury Shatillo, Nathalie Weidinger, Michael Desch","doi":"10.1007/s40268-026-00537-w","DOIUrl":"10.1007/s40268-026-00537-w","url":null,"abstract":"<p><strong>Background and objectives: </strong>Iclepertin, a selective GlyT1 inhibitor undergoes metabolism mainly via hepatic CYP3A4, with only a small fraction undergoing urinary excretion. Patients with kidney or liver problems can have reduced CYP3A4 levels or activity, which may affect the levels of iclepertin in the blood and, in turn, its safety. Here, we present the results of two studies investigating the safety and pharmacokinetics of iclepertin in participants with various degrees of renal or hepatic impairment.</p><p><strong>Methods: </strong>In these two phase I, open-label, non-randomised, parallel studies, a single oral dose of iclepertin 10 mg was administered to participants with mild, moderate or severe renal impairment or mild or moderate hepatic impairment, together with healthy matched participants (based on age, sex, weight and race [only for renal impairment]; n = 8 for each impairment group. Primary and secondary endpoints included maximum plasma concentration (C_max) and exposure metrics (area under the concentration-time curve [AUC]) of iclepertin. Safety was also assessed (adverse events [AEs]).</p><p><strong>Results: </strong>In the renal impairment study (N = 36), exposure of iclepertin was minimally affected by renal impairment across trial groups except for the severe renal impairment group, which showed increased iclepertin exposure (AUC_0-tz and AUC_0-∞ geometric mean ratio impaired versus matched participants [90% CI]: 126.1% [104.1, 152.8] and 146.0% [109.9, 193.9]), but similar C_max. In the hepatic impairment study (N = 29), participants with mild hepatic impairment showed similar C_max of iclepertin and exposure parameters to matched participants (geometric mean ratio [90% CI]: 102.1% [82.4, 126.4]), whereas participants with moderate hepatic impairment showed reduced C_max (geometric mean ratio impaired versus matched participants [90% CI]: 81.9% [67.2, 99.7]) and increased AUC_0-tz and AUC_0-∞ (128.7% [104.0, 159.3] and 157.2% [119.1, 207.5], respectively. Headache was the only drug-related AE reported in > 1 participant in each study, which was resolved within the treatment period, and no severe AEs were reported.</p><p><strong>Conclusions: </strong>These findings indicate that although some increased exposure to iclepertin is expected in patients with severe renal impairment or moderate hepatic impairment, iclepertin 10 mg demonstrated a favourable safety profile, was well-tolerated, and can be administered in patients with varying degrees of renal or hepatic impairment without dose modification.</p><p><strong>Study registration: </strong>ClinicalTrials.gov (NCT05718843, NCT05731895).</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"83-100"},"PeriodicalIF":2.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13076746/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147576533","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":"Treatment Outcomes with Lanadelumab Every 2 Weeks and Garadacimab are Very Similar in Patients with Hereditary Angioedema.","authors":"Irmgard Andresen, Natalie Khutoryansky, Sarah L Feeny, Alissa Dangel","doi":"10.1007/s40268-026-00539-8","DOIUrl":"10.1007/s40268-026-00539-8","url":null,"abstract":"","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"31-33"},"PeriodicalIF":2.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13076730/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147576479","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":"Updated Viloxazine Pharmacology: Experiments Establish Norepinephrine Transporter Occupancy and Serotonin 5-HT_2C, 5-HT_2B, and 5-HT₇ Receptor Binding at Therapeutically Relevant Concentrations.","authors":"Jennie Garcia-Olivares, Brittney Yegla, Jennifer Koch, Chungping Yu, Jonathan Rubin","doi":"10.1007/s40268-026-00543-y","DOIUrl":"10.1007/s40268-026-00543-y","url":null,"abstract":"<p><strong>Background and objectives: </strong>Viloxazine, which has been used to treat depression and attention-deficit/hyperactivity disorder (ADHD), has been termed a moderate-affinity, selective norepinephrine reuptake inhibitor based on high selectivity for norepinephrine relative to serotonin and dopamine transporters. However, accumulated research suggests a more complex mechanism of action, based on studies showing activity at serotonin 5-HT_2C, 5-HT_2B, and 5-HT₇ receptors, as well as findings that viloxazine increases extracellular serotonin (along with norepinephrine and dopamine) in the rat prefrontal cortex. This in vitro pharmacology study aimed to replicate and expand prior experiments to better characterize viloxazine's affinity for and activity at the norepinephrine transporter (NET) and individual serotonin receptors and to clarify how these effects contribute to the mechanism of action.</p><p><strong>Methods: </strong>Using in vitro binding competition and functional assays and ex vivo receptor occupancy studies in rats, we assessed viloxazine activity at human NET isoforms and 5-HT_2C, 5-HT_2B, and 5-HT₇ receptors relative to clinically relevant unbound viloxazine plasma concentrations (0.4-3.6 μM).</p><p><strong>Results: </strong>Viloxazine showed moderate binding affinity for NET (inhibition constant [K_i] = 0.13 µM) and 5-HT_2C (K_i = 0.66 µM), 5-HT_2B (K_i = 0.83 µM), and 5-HT₇ (K_i = 1.90 µM) receptors. In vitro functional studies showed viloxazine acted as a NET inhibitor, 5-HT_2C partial agonist, and 5-HT_2B and 5-HT₇ antagonist. At clinically relevant concentrations, viloxazine could potentially occupy nearly 95% of NET, more than 80% of 5-HT_2C and 5-HT_2B, and 65% of 5-HT₇ receptors. Subsequent ex vivo studies in rats confirmed high NET occupancy (67-94%) at clinically relevant concentrations.</p><p><strong>Conclusions: </strong>These results validate previous experiments showing that viloxazine, in addition to displaying high NET occupancy, acts as a partial agonist at 5-HT_2C receptors and an antagonist at 5-HT_2B and 5-HT₇ receptors at clinically relevant concentrations for ADHD treatment. Therefore, both NET inhibition and serotonin receptor activity may contribute to viloxazine's clinical efficacy. These findings are contributing to a renewed understanding of viloxazine's pharmacodynamic profile and likely multimodal mechanism of action.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"129-139"},"PeriodicalIF":2.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13076852/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147610332","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":"Advanced Drug Delivery Strategies for Overcoming Biological Barriers: Tumor Microenvironment and Blood-Brain Barrier.","authors":"Yicong Lei, Tingyu Xiao, Xin Hu, Huaqing Lin","doi":"10.1007/s40268-026-00538-9","DOIUrl":"10.1007/s40268-026-00538-9","url":null,"abstract":"<p><p>Therapeutic efficacy for malignancies and neurological disorders is fundamentally restricted by biological barriers, particularly the complex tumor microenvironment (TME) and selective blood-brain barrier (BBB). This review analyzes advanced drug delivery technologies engineered to overcome these obstacles. For TME penetration, stimuli-responsive nanocarriers enable spatiotemporally controlled drug release, while tumor-penetrating peptide functionalized nanoparticles enhance deep tumor diffusion; metal-organic frameworks further facilitate combinatorial therapy via microenvironment-triggered payload release. Regarding BBB transcendence, receptor-mediated transcytosis strategies significantly improve brain uptake, and physical-assisted approaches achieve localized barrier modulation. Bioinspired platforms-notably cell-membrane-coated nanoparticles and exosomes-demonstrate superior immune evasion and tissue-specific accumulation. Despite promising clinical progress exemplified by ANG1005 and focused ultrasound-assisted liposomal doxorubicin, translation challenges persist, including TME heterogeneity, scalable manufacturing complexities, and long-term biosafety. Future development prioritizes multifunctional theranostic systems integrating barrier-remodeling agents, artificial intelligence (AI)-optimized nanocarrier design, and sustainable manufacturing processes. Collectively, these innovations are transforming advanced drug delivery into a core therapeutic paradigm for intractable diseases.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"1-30"},"PeriodicalIF":2.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13076871/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147327964","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":"HIF-1α siRNA Enhances the Efficacy of Erlotinib in Non-small Cell Lung Cancer: A Novel Strategy to Reverse Hypoxia-Induced Drug Resistance.","authors":"Haojie Jiang, Shunhui Cai, Xiaojun Zhang, Shijie Chen, Chunyan Yue, Wu Yin, Yiqiao Hu","doi":"10.1007/s40268-025-00534-5","DOIUrl":"10.1007/s40268-025-00534-5","url":null,"abstract":"<p><strong>Background: </strong>Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality. While EGFR tyrosine kinase inhibitors (EGFR-TKIs) have improved survival, acquired resistance mediated by tumor hypoxia and HIF-1α stabilization often leads to treatment failure. This study investigated the regulatory role of HIF-1α in NSCLC drug resistance and evaluated a combined therapeutic strategy to overcome EGFR-TKI resistance.</p><p><strong>Methods: </strong>HIF-1α expression and downstream targets were assessed in H1975 and A549 cell lines using RT-qPCR and Western blot. Functional assays, including cell proliferation, apoptosis, invasion, lactate production, and ROS measurements, were performed following HIF-1α siRNA transfection and/or erlotinib treatment. Bioinformatics analyses of public datasets evaluated clinical relevance and pathway enrichment.</p><p><strong>Results: </strong>HIF-1α knockdown inhibited glycolysis, reduced lactate production, and alleviated hypoxia-induced oxidative stress. Combined treatment with HIF-1α siRNA and erlotinib synergistically suppressed cell proliferation, induced apoptosis, and inhibited invasion more effectively than single-agent treatments. Mechanistically, EGFR signaling positively regulated HIF-1α stability via the PI3K/AKT and MEK/ERK pathways. Bioinformatics confirmed that high HIF-1α expression correlates with poor prognosis in NSCLC patients.</p><p><strong>Conclusion: </strong>Targeting HIF-1α disrupts metabolic reprogramming and hypoxia adaptation, thereby enhancing erlotinib efficacy. This combined approach highlights the therapeutic potential of HIF-1α inhibition as a novel strategy to overcome EGFR-TKI resistance in NSCLC.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"101-115"},"PeriodicalIF":2.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13076752/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147610403","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":"Development and Evaluation of Multiple-Unit Tablets for the Controlled Release of Lornoxicam.","authors":"Yang Liu, Qiong-Zhi Shi, Yanchen Wang, Ze-Chun Long, Man Han, Yuan Zeng, Xiang-Yang Xie, Hui Liu","doi":"10.1007/s40268-026-00540-1","DOIUrl":"10.1007/s40268-026-00540-1","url":null,"abstract":"<p><strong>Background and objective: </strong>Lornoxicam (LOX) is a nonsteroidal anti-inflammatory drug used for pain management but requires frequent dosing due to its short half-life. This study aimed to develop a biphasic-release multiple-unit tablet (MUT) to achieve rapid and sustained LOX release with dose flexibility.</p><p><strong>Methods: </strong>LOX-loaded extended-release (ER) pellets were prepared by fluidized-bed coating of microcrystalline cellulose cores and optimized using a Box-Behnken design. The pellets were coated with Eudragit^® RL/RS and combined with an immediate-release (IR) component to form MUTs by conventional tableting. Pellets and tablets were evaluated for physicochemical properties and in vitro drug release.</p><p><strong>Results: </strong>Optimized ER pellets showed high drug-loading efficiency (92.2 ± 3%) and good mechanical properties. Drug release from ER pellets was best described by the Korsmeyer-Peppas model, indicating Fickian diffusion. The MUTs exhibited an initial LOX release of approximately 38%, followed by sustained release for 24 h, with > 90% cumulative release. Split tablets demonstrated release profiles comparable to intact tablets (f₂ > 50).</p><p><strong>Conclusion: </strong>The developed biphasic-release MUTs provide rapid onset, sustained LOX delivery, and reliable dose flexibility, representing a promising oral formulation for LOX therapy.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"51-70"},"PeriodicalIF":2.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13076759/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147436996","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":"Response to \"Treatment Outcomes with Lanadelumab Every Two Weeks and Garadacimab Are Very Similar in Patients with Hereditary Angioedema\".","authors":"Imtiaz A Samjoo","doi":"10.1007/s40268-026-00536-x","DOIUrl":"10.1007/s40268-026-00536-x","url":null,"abstract":"","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"35-37"},"PeriodicalIF":2.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13076817/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147576492","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":"Preclinical Evaluation of AHT-102, a CLDN18.2 × CD3 Bispecific Antibody: Pharmacokinetics, Anti-Tumor Efficacy, Tissue Distribution, and Safety Profile.","authors":"Huilun Chu, Guili Xu, Yunlong Liu, Niliang Qian, Yanchuan Li, Yujie Liu, Xiujie Pan, Xin Gao, Lun Ou, Junping Lv, Haifeng Song","doi":"10.1007/s40268-026-00535-y","DOIUrl":"10.1007/s40268-026-00535-y","url":null,"abstract":"<p><strong>Background and objectives: </strong>Claudin18.2 (CLDN18.2) is a promising therapeutic target overexpressed in various tumor tissues. While CD3-engaging bispecific antibodies show great potential, their clinical application is often limited by poor efficacy in solid tumors and significant safety risks, such as cytokine release syndrome (CRS). The objective of this study was to comprehensively evaluate the preclinical anti-tumor efficacy, pharmacokinetics, tissue distribution, and safety profile of AHT-102, a novel Fc-free CLDN18.2 × CD3 bispecific antibody with a low-affinity CD3 arm, to determine its potential for clinical development.</p><p><strong>Methods: </strong>This study evaluated the anti-tumor efficacy of AHT-102 in CLDN18.2-positive gastric cancer mouse models (NUGC4-CLDN18.2). We further assessed its pharmacokinetic characteristics, quantitative tissue distribution using ¹²⁵I-labeling, and long-term toxicity in human CD3EDG transgenic mice.</p><p><strong>Results: </strong>AHT-102 (0.1, 0.3, and 1 mg/kg) demonstrated significant dose-dependent anti-tumor effects, with tumor weight inhibition reaching 51% at the 1-mg/kg dose. Pharmacokinetic analysis in CD3EDG mice revealed linear characteristics with refined terminal half-lives of 0.762 h, 3.05 h, and 4.25 h for doses of 0.1, 0.5, and 2.5 mg/kg, respectively. Tissue distribution studies confirmed superior targeting specificity; the tumor-to-muscle ratio exceeded 15, and the molecule successfully bypassed the 'T-cell sink' by showing lower accumulation in the lymph nodes compared with the tumor. In vitro, AHT-102 did not induce target-independent cytokine release from peripheral blood mononuclear cells (PBMCs). The maximum tolerated dose (MTD) in human CD3EDG mice reached 13.65 mg/kg, a 136.5-fold margin over the projected clinical starting dose. Observed gastric tissue damage was dose-dependent and reversible upon drug discontinuation.</p><p><strong>Conclusions: </strong>AHT-102, a novel Fab-like bispecific antibody, achieves an optimized therapeutic balance through its low-affinity CD3 arm and Fc-free format. It demonstrates significant anti-tumor efficacy and exceptional targeting specificity while avoiding systemic immunotoxicity typically associated with CD3-targeting agents. These findings provide a robust scientific rationale for the clinical translation of AHT-102 in patients with CLDN18.2-positive cancers.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"39-50"},"PeriodicalIF":2.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13076708/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147291539","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":"Pharmacokinetics and Bioequivalence Evaluation of Piracetam Tablet: A Randomized, Single-Dose, Two-Period, Crossover Study in Healthy Chinese Participants Under Fasting and Fed Conditions.","authors":"Hegui Yan, Ming Zhou, Zhixiang Pan, Yu Peng, Jie Wang, Xiuwen Li, Yafang Xie, Qianying Liu, Cuiping Huang, Qiuhong Wang, Guan Liu","doi":"10.1007/s40268-026-00541-0","DOIUrl":"10.1007/s40268-026-00541-0","url":null,"abstract":"<p><strong>Background: </strong>Piracetam, a nootropic drug, is widely used for treating cognitive impairments. However, pharmacokinetic and bioequivalence data for piracetam formulations in the Chinese population are limited. This study was conducted to evaluate the pharmacokinetics and bioequivalence of a newly developed generic piracetam tablet compared with the reference product (Nootropyl^®) in healthy Chinese participants under fasting and fed conditions.</p><p><strong>Methods: </strong>A randomized, open-label, single-dose, two-period, two-sequence crossover study was conducted in healthy Chinese participants under fasting and fed conditions. Healthy participants received a single oral dose of piracetam 800 mg as either the test or reference formulation, followed by a 7-day washout period. Plasma piracetam concentrations were determined using a validated high-performance liquid chromatography-tandem mass spectrometry method. Pharmacokinetic parameters, including maximum plasma concentration (C_max), area under the plasma concentration-time curve from time zero to the last measurable concentration (AUC_0-t), and area under the plasma concentration-time curve extrapolated to infinity (AUC_0-∞), were calculated using non-compartmental analysis. Bioequivalence was assessed by calculating the 90% confidence intervals (CIs) of the geometric mean ratios (GMRs) for C_max, AUC_0-t, and AUC_0-∞.</p><p><strong>Results: </strong>56 participants were enrolled, with 28 participants completing each study under fasting and fed conditions. Under fasting conditions, the 90% confidence intervals (CIs) of the GMRs for C_max, AUC_0-t, and AUC_0-∞ were 98.53%, 98.40%, and 98.49%, respectively. Under fed conditions, the corresponding 90% CIs were 99.31%, 99.03%, and 99.01%. All values were within the predefined bioequivalence acceptance range of 80-125%. Food intake reduced the rate of absorption, as indicated by a lower C_max and delayed time to maximum concentration (T_max), without affecting the extent of absorption. Both formulations were well tolerated, and no serious adverse events were reported.</p><p><strong>Conclusions: </strong>The test piracetam tablet was demonstrated to be bioequivalent to the reference formulation with respect to the rate and extent of absorption under both fasting and fed conditions in healthy Chinese participants. The comparable safety and tolerability profiles support the clinical interchangeability of the generic and reference piracetam formulations.</p><p><strong>Clinical trial registration: </strong>CTR20213027.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"71-81"},"PeriodicalIF":2.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13076839/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147482364","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":"Arylpiperazine Derivative NAF19 Inhibits Prostate Cancer Activity and Its Molecular Mechanisms.","authors":"Hua Jiang, Mingzhen Xu, Songsong Jiang, Weiqiang Huang","doi":"10.1007/s40268-026-00542-z","DOIUrl":"10.1007/s40268-026-00542-z","url":null,"abstract":"<p><strong>Background and objectives: </strong>Androgen deprivation therapy (ADT) remains the primary treatment for advanced prostate cancer. However, most patients relapse within 18-24 months, progressing to castration-resistant prostate cancer (CRPC) which is currently incurable. Our preliminary studies identified the arylpiperazine derivative NAF19 as a promising therapeutic agent against prostate cancer, though its precise mechanisms remained unclear. This study aims to systematically evaluate the antitumor effects of NAF19 in prostate cancer cells and elucidate its molecular mechanisms, with a focus on its multi‑target inhibition of the AR/AR‑Vs signaling pathway and key survival pathways.</p><p><strong>Methods: </strong>To evaluate the effects of NAF19 on prostate cancer cell growth, we treated a panel of prostate cancer cell lines (LNCaP, C4-2, 22Rv1, DU145, and PC-3) representing both androgen-sensitive and castration-resistant phenotypes (including AR-expressing and AR-null subtypes) with varying concentrations of NAF19 for 72 h. Cell viability and sensitivity were subsequently assessed using the CCK-8 assay. In LNCaP and 22Rv1 cells, we further performed qRT-PCR to analyze the mRNA expression levels of AR/AR-Vs and their downstream target genes (PSA and UBE2C), flow cytometry to determine cell cycle distribution, and western blotting to examine the levels of cleaved PARP, antiapoptotic Bcl-2 family proteins, phosphorylated AKT (at Ser473 and Thr308), phosphorylated ERK, phosphorylated S6, as well as total AR and AR-V7. To assess the impact of NAF19 on tumor cell metastatic potential and proliferation, transwell migration and invasion assays, along with EdU incorporation assays, were conducted. Furthermore, a luciferase reporter assay was carried out to evaluate the transcriptional activity of the androgen receptor (AR).</p><p><strong>Results: </strong>NAF19 exhibited growth-inhibitory effects across all five prostate cancer cell lines. It significantly suppressed AR/AR-Vs downstream gene expression, induced G1-phase cell cycle arrest in 22Rv1 cells, and reduced anti-apoptotic Mcl-1 protein levels while activating apoptosis. NAF19 dose-dependently induced PARP cleavage; NAF19 significantly reduced the phosphorylation levels of AKT (at T308 and S473 sites), ERK, and S6. Functional assays confirmed marked suppression of migration, invasion, and proliferation in NAF19-treated cells.</p><p><strong>Conclusions: </strong>The novel arylpiperazine derivative NAF19 exerts multi-targeted antitumor effects by concurrently inhibiting AR/AR-Vs signaling pathways and activating apoptotic cascades, thereby potently suppressing the migratory, invasive, and proliferative capacities of prostate cancer cells.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"117-128"},"PeriodicalIF":2.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13076722/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147610397","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}