ACS Pharmacology and Translational Science最新文献

{"title":"High-Quality In Vivo Chemical Probes for Protein Kinases Disclosed in 2024","authors":"Ricardo A. M. Serafim*,&nbsp; and ,&nbsp;Matthias Gehringer*,&nbsp;","doi":"10.1021/acsptsci.5c00293","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00293","url":null,"abstract":"<p >Protein kinases are highly relevant drug targets, yet a significant fraction of the human kinome remains underexplored. Highly potent and selective small-molecule inhibitors used as chemical probes are invaluable tools for enabling the validation and translation of new kinase targets. This review provides an overview and analysis of the high-quality in vivo chemical probes for protein kinases published and deposited at the Chemical Probes Portal in the year 2024. We discuss the design strategies, molecular mechanism of action, details of their use in vitro and in vivo, as well as their application in target (in)validation. We also highlight the importance of wisely selecting chemical probes and encourage best practices in using such tool compounds.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 8","pages":"2401–2414"},"PeriodicalIF":3.7,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsptsci.5c00293","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144806676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Teniposide Triggers DNA Repair Inhibition by Binding and Ubiquitination of Apurinic/Apyrimidinic Endonuclease 1 to Boost Oxidative DNA Damage for Lung Cancer Destruction","authors":"Ning Han,&nbsp;Jun Hu,&nbsp;Zhong-Xiong Xie,&nbsp;Lei Zhang,&nbsp;Liu-Gen Li,&nbsp;Xin-Ran Yu,&nbsp;Cunqing Kong,&nbsp;Fan Leng,&nbsp;Cui Hu,&nbsp;Qiufang Zhang*,&nbsp;Mei-Fang Wang* and Tong-Fei Li*,&nbsp;","doi":"10.1021/acsptsci.5c00308","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00308","url":null,"abstract":"<p >Teniposide (Ten/VM-26) is low in toxicity and has proven to be effective in destroying malignant cells at low doses. However, the target and molecular mechanism of Ten/VM-26 are poorly understood, which limits its clinical application against solid malignant cancers. Apurinic/apyrimidinic endonuclease 1 (APEX1) expression is upregulated in lung cancer, which could effectively suppress DNA damage. The present study aims to explore how Ten/VM-26 regulates APEX1 and thereby exploits its antilung cancer effects. Ten/VM-26 possessed powerful antilung cancer efficacy <i>in vitro</i> and organoid models. Furthermore, the findings of <i>in vivo</i> experiments evidenced that Ten/VM-26 could suppress the growth of tumor grafts without impacting the vital organs or body weight of mice. RNA-sequence analysis revealed that Ten/VM-26 treatment led to differentially expressed genes (DEGs), which were enriched in the DNA damage-associated biological process (BP). Reactive oxygen species (ROS) generation mediated by Ten/VM-26 was the major contributor to its anticancer effect. The in-depth investigation identified that APEX1 was efficiently expressed in lung cancer tissues, leading to a poor prognosis. Interestingly, APEX1 was downregulated in the presence of Ten/VM-26, which further abolished the protection of DNA, resulting in robust DNA damage. Further findings discovered that Ten/VM-26 could bind to APEX1 and thereby dampen its function. In contrast, APEX1 recovery attenuated the Ten/VM-26-induced DNA damage and anticancer efficacy. In summary, these data make a strong argument for the notion that Ten/VM-26-mediated inhibition of APEX1 contributes to DNA damage and thereby achieves favorable antilung cancer effects, wherein Ten/VM-26 could down-regulate APEX1 by binding and ubiquitination. The current study presents a critical target and mechanism for Ten/VM-26-mediated antilung cancer therapy.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 8","pages":"2710–2724"},"PeriodicalIF":3.7,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144806348","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of 6-Aryl-7-Deazapurine Ribonucleoside Phosphonates as Inhibitors of Ecto-5′-Nucleotidase (CD73)","authors":"Magdalena Šímová,&nbsp;Tereza Ormsby,&nbsp;Ugnė Šinkevičiu̅tė,&nbsp;Lucia Sirotová Veselovská,&nbsp;Kateřina Čermáková,&nbsp;Martin Hadzima,&nbsp;Lenka Bartoň,&nbsp;Jana Staňurová,&nbsp;Anežka Kramná,&nbsp;Pavel Šácha,&nbsp;Michal Tichý,&nbsp;Michal Hocek,&nbsp;Jan Konvalinka* and Kristyna Blazkova*,&nbsp;","doi":"10.1021/acsptsci.5c00180","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00180","url":null,"abstract":"<p >CD73 is a crucial regulator of adenosine production in the tumor microenvironment and, therefore, represents a valuable target for cancer immunotherapy. While different inhibitors of CD73 have been studied, the progress remains hindered by a lack of high-throughput assays that would allow the screening of large chemical libraries. Establishing a sensitive assay for the detection of CD73 activity could enable additions to the CD73 inhibitor chemical space as well as help facilitate a better understanding of the CD73 reaction mechanism. In this study, we focused on the development and adaptation of DIANA for CD73 high-throughput screening and showed that we can detect enzyme inhibition with high sensitivity. We then used this assay to screen an IOCB library, a proprietary set of chemical compounds with a special focus on nucleotide analogues. We identified several scaffolds that inhibit CD73 and in an SAR study demonstrated fine-tuning of the inhibition properties of monophosphonate analogues. Moreover, using a breast cancer cell line as a model with endogenous CD73 expression, we demonstrated the inhibition of CD73 directly on cells. The establishment of a sensitive assay for the detection of CD73 activity allowed us to develop potent inhibitors of the enzyme with low nanomolar inhibition constants. Our findings further promote the importance of CD73 inhibitors in cancer therapy.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 8","pages":"2575–2585"},"PeriodicalIF":3.7,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsptsci.5c00180","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144806707","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Technetium-99m-Labeled Fibroblast Activation Protein-Targeted Nanobody Radiotracer: from Preclinical Development to Clinical Translation in Cancer Imaging","authors":"Chenzhen Li,&nbsp;Xinru Li,&nbsp;Yuchen Wang,&nbsp;Zhidong Bai,&nbsp;Yuanbo Wang,&nbsp;Rui Gao and Bing Jia*,&nbsp;","doi":"10.1021/acsptsci.5c00256","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00256","url":null,"abstract":"<p >Fibroblast activation protein (FAP) is a highly expressed marker in cancer-associated fibroblasts (CAFs) across various epithelial cancers, making it an attractive target for diagnostic imaging. To address the limitations of existing FAP-targeted radiopharmaceuticals, such as poor tumor retention and off-target uptake, this study aimed to establish a comprehensive FAP nanobody library. Through systematic screening, we sought to identify a nanobody with cross-reactivity to both human and murine FAP, optimized for technetium-99m (^99mTc) labeling, and suitable for single-photon emission computed tomography (SPECT) imaging. A library of anti-FAP nanobodies (AFNs) was constructed and screened for binding affinity and specificity to human and murine FAP. Selected nanobodies were labeled with ^99mTc using a site-specific radiolabeling process. In vitro assays were conducted to evaluate binding kinetics and cross-reactivity, while in vivo studies assessed pharmacokinetics, biodistribution, and imaging performance in murine tumor models. Finally, a first-in-human clinical study was performed to validate the safety and diagnostic efficacy of the lead nanobody-based radiotracer. From the nanobody library, three candidates were identified with high specificity for FAP: AFN01 (murine-specific), AFN05 (human-specific), and AFN13 (cross-reactive to both human and murine FAP). Among them, [^99mTc]Tc-AFN13 demonstrated excellent binding affinity (dissociation constants: 2.16 ± 0.16 nM for murine FAP and 6.82 ± 0.54 nM for human FAP) and favorable pharmacokinetics. In vivo SPECT imaging revealed rapid tumor accumulation, prolonged retention, and minimal off-target uptake (e.g., tumor uptake of 4.41 ± 0.13% ID/cc at 30 min postinjection, declining to 2.35 ± 0.17% ID/cc at 12 h). Preliminary clinical imaging in patients confirmed the safety and specificity of [^99mTc]Tc-AFN13 for FAP-expressing lesions, with no adverse events observed. In conclusion, this study successfully established a FAP nanobody library and identified [^99mTc]Tc-AFN13 as a novel radiotracer with cross-reactivity to human and murine FAP. Its robust preclinical performance and promising clinical results highlight its potential for SPECT imaging in FAP-expressing cancers, paving the way for further clinical translation and theranostic applications.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 8","pages":"2673–2682"},"PeriodicalIF":3.7,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144806397","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis and Preclinical Evaluation of Dual-Targeted Molecular Tracer for Positron Emission Tomography Imaging of Programmed Cell Death Ligand-1 and Integrin αvβ3","authors":"Yuxuan Zhou,&nbsp;Manxuan Ge,&nbsp;Xinru Li,&nbsp;Quan Xie,&nbsp;Miao Sun,&nbsp;Ke Li,&nbsp;Huijie Jiang*,&nbsp;Jianguo Lin* and Ling Qiu*,&nbsp;","doi":"10.1021/acsptsci.5c00036","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00036","url":null,"abstract":"<p >Dual-targeting strategies have shown considerable potential in improving the imaging contrast and specificity toward tumor tissues. In this study, we synthesized a dual-targeted tracer, <b>[</b>^<b>68</b><b>Ga]Ga-NOTA-IMB-RGD</b>, which synergistically targeted programmed cell death ligand-1 (PD-L1) and integrin α_vβ₃. The tracer was produced with high radiochemical purity (&gt;95%) and radiochemical yield (&gt;95%). <i>In vitro</i> cellular uptake studies revealed that <b>[</b>^<b>68</b><b>Ga]Ga-NOTA-IMB-RGD</b> exhibited high binding affinity for both PD-L1 and α_vβ₃, resulting in significantly higher uptake in PD-L1- and α_vβ₃-positive cells (U87, A375-hPD-L1, B16–F10, and MC38) compared to α_vβ₃-positive (A375) or PD-L1- and α_vβ₃-negative (LLC) cells. <i>In vivo</i> imaging of <b>[</b>^<b>68</b><b>Ga]Ga-NOTA-IMB-RGD</b> in tumor-bearing mice revealed high and specific tumor uptake in double-positive tumors, modest tumor uptake in single-positive tumors, and low uptake in double-negative tumors, indicating strong binding to both PD-L1 and α_vβ₃ <i>in vivo</i>. <i>Ex vivo</i> tissue analysis further validated the high specificity and sensitivity of <b>[</b>^<b>68</b><b>Ga]Ga-NOTA-IMB-RGD</b> in detecting tumors coexpressing PD-L1 and α_vβ₃. Importantly, <b>[</b>^<b>68</b><b>Ga]Ga-NOTA-IMB-RGD</b> exhibited enhanced tumor uptake and retention compared to both PD-L1-targeted and α_vβ₃-targeted tracers in the same tumor models. In conclusion, the dual-targeted tracer <b>[</b>^<b>68</b><b>Ga]Ga-NOTA-IMB-RGD</b> was successfully prepared and showed significantly specific targeting of both PD-L1 and α_vβ₃ <i>in vivo</i>, offering promising potential for clinical translation.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 8","pages":"2465–2473"},"PeriodicalIF":3.7,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144806371","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Causal Role of Consciousness in Psychedelic Therapy for Treatment-Resistant Depression: Hypothesis and Proposal","authors":"Tobías Fernández-Borkel,&nbsp;Lucas F. Borkel,&nbsp;Jaime Rojas-Hernández,&nbsp;Elisa Hernández-Álvarez,&nbsp;Domingo J. Quintana-Hernández,&nbsp;Ludovica G. Ponti and Luis Alberto Henríquez-Hernández*,&nbsp;","doi":"10.1021/acsptsci.5c00445","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00445","url":null,"abstract":"<p >The therapeutic potential of psychedelic substances, particularly psilocybin, for treatment-resistant depression (TRD) has garnered considerable attention. However, the necessity of subjective psychedelic experiences for therapeutic efficacy remains unclear, creating a critical gap in the field. To determine whether subjective psychedelic experiences induced by psilocybin are required for its antidepressant effects or whether these effects are mediated solely by neurobiological actions independent of consciousness. We propose a randomized controlled trial with three groups: (P) Psilocybin (25 mg oral dose with guided therapeutic integration), (P+A) Psilocybin under propofol-induced general anesthesia (eliminating subjective experiences), and (X+A) Propofol-induced anesthesia with placebo (with no psilocybin). Clinical assessments of depression and anxiety, combined with fMRI-based brain connectivity analysis (including fractal complexity, brain entropy, and network dynamics), will be conducted at baseline, postintervention, and during follow-ups. The proposed study protocol expects distinct therapeutic outcomes across groups. Superior improvements in depression and anxiety symptoms are anticipated in the conscious psilocybin group (P) compared to both anesthetized groups (P+A) and (X+A). Additionally, increased brain connectivity measures in fractal complexity and entropy are hypothesized to correlate positively with therapeutic improvements, particularly pronounced in the conscious condition. Isolating subjective experiences through anesthesia, aims to determine whether conscious psychedelic experiences play a causal role in therapeutic outcomes. Results have significant implications for clinical protocols, treatment guidelines, and the broader theoretical understanding of consciousness and its relationship to mental health.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 8","pages":"2839–2847"},"PeriodicalIF":3.7,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsptsci.5c00445","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144806462","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Body Recomposition Effects of Long-Term Glycyrrhizin Consumption in Nonobese Individuals: From the Clinic to the Bench","authors":"Yang-Ching Chen,&nbsp;Yu-Cih Huang,&nbsp;Yu-Jie Cheng,&nbsp;Jessika Woo Kar Man,&nbsp;Rong-Hong Hsieh,&nbsp;Shih-Yuan Hsu and Yue-Hwa Chen*,&nbsp;","doi":"10.1021/acsptsci.5c00120","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00120","url":null,"abstract":"<p >Non-nutritive sweeteners are used for obesity management, but their benefits and risks are unclear. Artificial sweeteners may harm cardiovascular health, while natural sweeteners like glycyrrhizin offer potential benefits. This study examined long-term glycyrrhizin consumption’s effects on body composition in adolescents and mice, comparing obese and normal-weight individuals and exploring underlying mechanisms. Data from the Taiwan Pubertal Longitudinal Study (TPLS) (<i>n</i> = 1641) were analyzed, and experiments with C57BL/6 mice and 3T3-L1 preadipocytes were conducted. Higher glycyrrhizin consumption correlated with lower body fat and higher fat-free mass in adolescents, especially nonobese individuals. In mice, glycyrrhizin supplementation reduced adipose tissue weight and serum leptin and cholesterol levels and increased muscle weight and MyoG mRNA expression. Cell experiments showed that glycyrrhizin inhibited adipocyte differentiation and lipid accumulation in preadipocytes. The mechanism involved reduced expression of mRNAs such as C/EBPα, GLUT4, leptin, and adiponectin. Glycyrrhizin consumption may reduce adiposity and increase muscle mass in nonobese individuals by inhibiting adipocyte differentiation. These findings suggest that glycyrrhizin influences body composition by reducing fat mass and increasing muscle mass in nonobese individuals, warranting further clinical studies.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 8","pages":"2536–2547"},"PeriodicalIF":3.7,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsptsci.5c00120","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144806295","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transport of Small Aliphatic Amines by Polyspecific Solute Carriers: Deciphering Structure–Function Relationships","authors":"Wouroud Ismail Al-Khalil,&nbsp;Jürgen Brockmöller and Muhammad Rafehi*,&nbsp;","doi":"10.1021/acsptsci.5c00340","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00340","url":null,"abstract":"<p >Membrane proteins of the solute carrier (SLC) 22A and 47A families are polyspecific transporters critical for handling diverse endogenous and exogenous compounds, including many clinically relevant drugs. However, their substrate specificity remains poorly understood. To address this, we conducted a structure–function relationship analysis focusing on small aliphatic amines (alkylamines and alkanolamines) and enantioselectivity of their transport. Using HEK293 cells stably overexpressing organic cation transporters (OCT) 1, 2, or 3 (<i>SLC22A1</i>, <i>-2</i>, or <i>-3</i>) or multidrug and toxin extrusion transporters (MATE) 1 or 2-K (<i>SLC47A1</i> and <i>-2</i>), substrate transport was quantified through liquid chromatography─tandem mass spectrometry, with 6-aminoquinolyl-<i>N</i>-hydroxysuccinimidyl carbamate derivatization as needed. While most tested compounds exhibited physicochemical properties consistent with typical OCT and MATE substrates, compounds with a molecular weight of less than 145 Da were mostly not transported by OCT1, OCT3, or the MATEs. However, in great contrast, OCT2 demonstrated robust transport of small aliphatic amines and alkanolamines (molecular weight of 60–145 Da), with modest stereoselectivity favoring (<i>S</i>)-enantiomers. Structural complexity, such as carbon chain length and amino group positioning, strongly influenced transport activity and kinetics, while compounds with more than two positive charges at different positions were not transported. Additionally, we identified a novel role for OCT2 as an efficient efflux transporter for ethanolamine. These findings reveal critical molecular determinants underlying SLC-mediated transport, enhancing our understanding of OCT and MATE substrate preferences and mechanisms. This knowledge provides a foundation for better predicting transporter interactions and optimizing drug design.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 8","pages":"2777–2794"},"PeriodicalIF":3.7,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsptsci.5c00340","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144806437","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Crossing Barriers: Advancements in Macromolecular Therapeutics for Neurodegenerative Diseases and Strategies to Overcome the Blood–Brain Barrier","authors":"Bekas Alo,&nbsp; and ,&nbsp;Christina Lamers*,&nbsp;","doi":"10.1021/acsptsci.5c00153","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00153","url":null,"abstract":"<p >Neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis, present considerable challenges for our societies and health systems due to their progressive nature, the demographic shift toward older populations, and limited treatment options. Recent advances in macromolecular therapeutics, including antibodies, peptides, and proteins, offer novel therapeutic modalities for a broad range of diseases. Their high potency and specificity hold promise for disease-modifying therapies to combat neurodegenerative diseases. However, the blood–brain barrier poses a significant challenge for the effective delivery of these large molecules to the central nervous system. This review discusses the physiological role of the blood–brain barrier and its influence on restricting the exposure of macromolecules in the brain. Furthermore, emerging strategies for enhancing blood–brain barrier permeability to macromolecules are highlighted. This review summarizes modifications designed to utilize receptor-mediated uptake, adsorptive-mediated transcytosis, carrier-mediated transport, and nanoparticle-based delivery systems to overcome the blood–brain barrier. Additionally, we emphasize the importance of testing macromolecular therapeutics for their blood-brain barrier permeability and review the methods for such <i>in vitro</i> and <i>in vivo</i> testing. Finally, we shed light on therapeutics in preclinical and clinical development for neurodegenerative diseases and their challenges.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 8","pages":"2353–2383"},"PeriodicalIF":3.7,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsptsci.5c00153","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144806198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of Anticancer Indole-Based 4,5-Dihydroisoxazole Derivative with Selectivity toward Leukemia Cells","authors":"Monika Majirská,&nbsp;Zuzana Kudličková,&nbsp;Natália Nosálová,&nbsp;Martin Kello,&nbsp;Radka Michalková,&nbsp;Danica Sabolová,&nbsp;Monika Tvrdoňová,&nbsp;Dávid Jáger,&nbsp;Martina Bago Pilátová*,&nbsp;Martin Vojtek* and Carmen Diniz,&nbsp;","doi":"10.1021/acsptsci.5c00103","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00103","url":null,"abstract":"<p >Isoxazole-derived compounds possess various bioactivities including anticancer, immunomodulatory, antimicrobial, anti-inflammatory, or antipsychotic effects with successful implementation in clinical practice. Treatment of hematological malignancies with isoxazole derivatives represents a promising area of research. The present study aimed to synthesize 11 novel 3,5-diaryl-4,5-dihydroisoxazole compounds and assess their antiproliferative effects using cell viability assay in a panel of nine cancer types including breast (MCF-7), colon (HCT-116), cervical (HeLa), lung (A549), ovarian cancer (A2780), glioblastoma (U87), hepatocellular carcinoma (HepG2), and leukemia (Jurkat and HL-60) cells as well as two noncancerous cell lines (Bj-5ta and MCF-10A). The most promising compound was further screened using flow cytometry, Western blot, fluorescence microscopy, and chemotaxis/migration cell assays. Compound (±)-3-[3-(4-bromophenyl)-4,5-dihydro-1,2-oxazol-5-yl]-1-methyl-1<i>H</i>-indole (<b>4a, DHI1</b>) showed the most promising potential due to its high selectivity toward leukemia Jurkat and HL-60 cells while having at the same time minimal toxicity to noncancerous cells as well as healthy human peripheral blood mononuclear cells. For the first time, <b>DHI1</b> was shown to inhibit the migration and invasiveness of Jurkat and HL-60 cells via disruption of cytoskeletal actin filaments coupled to G2/M cell cycle arrest in Jurkat and HL-60 cells and S phase arrest in HL-60 cells. Treatment with <b>DHI1</b> affected signaling proteins associated with the cell cycle, including p21, Cyclin B1, Cdc2, Wee1, Rb, and Chk1. The binding interaction between <b>DHI1</b> and BSA revealed that the Stern–Volmer constant (<i>K</i>_sv) for BSA fluorescence quenching increases with temperature, rising from 8.06 × 10⁴ to 11.09 × 10⁴ M^–1. Herein, the novel synthesized indolyl dihydroisoxazole derivative <b>DHI1</b> possesses promising therapeutic potential and superior safety profile due to its high selectivity toward Jurkat and HL-60 leukemia cells and low toxicity to noncancerous cells.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 8","pages":"2507–2525"},"PeriodicalIF":3.7,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144806159","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}