ACS Pharmacology and Translational Science最新文献

{"title":"Screening for Antileukemia Agents in FMS-like Tyrosine Kinase 3 (FLT3)-Mutated Acute Myeloid Leukemia Cells","authors":"Livia Bassani Lins de Miranda,&nbsp;Wítor Ribeiro Ferraz,&nbsp;Keli Lima,&nbsp;Jorge Antonio Elias Godoy Carlos,&nbsp;Fernando Moura Gatti,&nbsp;Rodrigo Heleno Alves,&nbsp;Gustavo Henrique Goulart Trossini* and João Agostinho Machado-Neto*,&nbsp;","doi":"10.1021/acsptsci.5c00317","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00317","url":null,"abstract":"<p >Acute myeloid leukemia (AML) remains a challenging hematological malignancy due to its genetic heterogeneity, high relapse rates, and limited therapeutic options for refractory cases. FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (FLT3-ITD) mutations are among the most frequent genetic alterations in AML, associated with poor prognosis and treatment resistance. In this study, we investigated the antileukemic potential of compound HI042, identified from a library of 78 molecules, focusing on its effects on FLT3-ITD-mutated AML models. HI042 selectively reduced the viability of FLT3-ITD-positive cell lines, induced apoptosis, disrupted cell cycle progression, and diminished the clonogenic potential. Chemoinformatics analysis revealed structural similarities between HI042 and retinoic acid analogues, known for their differentiation-inducing effects. Consistently, HI042 treatments increased the level of differentiation markers, including CD11b and transcription factors such as PU.1 and C/EBPs, particularly in MOLM-13 cells. Furthermore, combining HI042 with the FLT3 inhibitor quizartinib synergistically enhanced apoptosis and reduced cell proliferation. These findings highlight HI042’s dual activity in inducing differentiation and apoptosis while synergizing with established therapies. Overall, HI042 emerges as a promising candidate for targeted therapies against FLT3-ITD-mutated AML, addressing a critical need for novel treatment strategies for this high-risk AML subgroup.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 8","pages":"2756–2766"},"PeriodicalIF":3.7,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsptsci.5c00317","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144806800","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":"3-Phenethyl-2-phenylquinazolin-4(3H)-one Inhibits Breast Cancer Cell Motility, Energy Metabolism, and Proliferation by Inactivating Phosphoinositide 3-Kinase/Protein Kinase B and Epidermal Growth Factor Receptor Pathways","authors":"Rui Zhou,&nbsp;Eun-Young Lee,&nbsp;Prima F. Hillman,&nbsp;Sang-Jip Nam* and Hangun Kim*,&nbsp;","doi":"10.1021/acsptsci.5c00133","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00133","url":null,"abstract":"<p >Marine-derived compounds hold great promise for cancer therapy, targeting various essential processes in cancer progression, such as apoptosis, metastasis, proliferation, and drug resistance. 3-Phenethyl-2-phenylquinazolin-4(3<i>H</i>)-one (<b>1</b>) is a natural quinazolinone derivative extracted from the marine sediment-derived genus <i>Acremonium</i> sp. CNQ-049. This study explores the therapeutic effects and underlying mechanisms of <b>1</b> in breast cancer. Compound <b>1</b> significantly inhibited epithelial–mesenchymal transition by downregulating EMT-related transcription factors as well as cancer metabolism by reducing the expression of glycolytic enzymes. By targeting protein kinase B (AKT1) and epidermal growth factor receptor (EGFR), compound <b>1</b> decreased the expression of p-AKT, p-EGFR, p-STAT3, p-NF-κB, β-catenin, and estrogen receptor, along with their downstream targets c-Myc and cyclin-D1, thereby inhibiting breast cancer cell motility, proliferation, and energy metabolism. In an orthotopic mouse model of breast cancer, treatment with <b>1</b> effectively inhibited tumor growth and downregulated associated target genes <i>in vivo</i>. Compound <b>1</b> exerted potent anticancer activity against breast cancer (BC) cells <i>in vitro</i> and effectively inhibited tumor growth in an orthotopic mouse model. Overall, suppression of both EMT and reprogramming of cancer metabolism metabolic pathways by inactivating phosphoinositide 3-kinase (PI3K)/AKT and EGFR pathways suggested that <b>1</b> could be a potential therapeutic agent for BCs. Notably, <b>1</b> represents a promising therapeutic effect against hormone-dependent (ER-positive) BCs.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 8","pages":"2548–2563"},"PeriodicalIF":3.7,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144806989","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":"Mechanically Active and Antimicrobial Wound Closure Using an Adhesive Hydrogel-Elastomer","authors":"Cynthia Liu,&nbsp;Bersa Kelkai,&nbsp;David Wu,&nbsp;Alexander Tatara,&nbsp;Juan Cintron,&nbsp;David J. Mooney* and Benjamin R. Freedman*,&nbsp;","doi":"10.1021/acsptsci.5c00341","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00341","url":null,"abstract":"<p >Chronic wounds affect millions worldwide and lead to pain, infection, and impaired quality of life. Current wound sealing technologies for chronic wound care remain largely palliative, with poor adhesion, weak mechanical properties, and limited ability to deliver therapeutics. Emerging technologies, including autologous blood products, growth factor-enhanced scaffolds, and artificial skin, although clinically successful, are limited from widespread adoption by the high cost of production and challenging clinical workflow. Here, we present a tough adhesive-elastomer wound care technology that is mechanically robust to approximate wound edges, can adhere strongly to wet and dynamic wound surfaces, is capable of delivering antimicrobials, and supports cell migration and proliferation. This technology has the potential to address an unmet clinical need in wound healing.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 8","pages":"2795–2803"},"PeriodicalIF":3.7,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144806783","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":"Plant-Derived Exosome-Coated Niosome Oxygen Nanobubbles for the Mitigation of Ocular Ischemia","authors":"Anika Bushra,&nbsp;Moussa Fall,&nbsp;Wen Ren,&nbsp;Jimoh Igbalaye and Joseph Irudayaraj*,&nbsp;","doi":"10.1021/acsptsci.5c00363","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00363","url":null,"abstract":"<p >Ischemic and/or hypoxic ocular diseases lack adequate, effective mitigative approaches and an understanding of the fundamental causes of ischemia-induced tissue damage. In this work, we introduce a plant-derived exosome-coated niosome oxygen nanobubble (E-NON), consisting of a gaseous oxygen core encapsulated within dual shells. The niosome inner shell is composed of Pluronic F-127, polysorbate 80, and medium chain triglyceride (MCT) oil, all of which are FDA approved for ophthalmic indications. The outer shell consists of exosomes derived from <i>Withania somnifera</i> (ashwagandha) fruits, which are known for their antioxidant and anti-inflammatory properties. The hydrodynamic diameter of conceived E-NONs is 85.6 ± 14.4 nm with a zeta (ζ)-potential of −19.3 ± 0.8 mV, and oxygen loading capacity of 56.4 ± 0.9 mg/L. The E-NON formulation was stable in sealed glass vials for up to 3 months at 4 °C and yields a controlled release profile extending up to 16 h under hypoxic conditions. The therapeutic efficacy of E-NONs for hypoxia mitigation was evaluated in retinal epithelium (ARPE19) and uveal melanoma (MP46) cell lines, both demonstrating excellent hypoxia recovery. Moreover, RT-qPCR results verified downregulation of genes related to hypoxia (HIF-1α, VEGF-A, EPO, PAI-1) and oxidative stress (Nrf2, NQO1, HO-1) after treatment with 10 (v/v%) E-NONs. Additionally, an in vivo safety evaluation in a rabbit model indicated that the formulation was safe for intravitreal administration. We propose that our novel oxygen delivery platform is an effective tool for hypoxia mitigation and can be utilized to treat ischemic conditions in the eye.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 8","pages":"2814–2829"},"PeriodicalIF":3.7,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144806850","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":"Optimization and Evaluation of Complementary Degrader Discovery Assays for Application in Screening","authors":"Johanna Huchting*,&nbsp;Arjen Weller,&nbsp;Moyra Schweizer,&nbsp;Mona Brandt,&nbsp;Jan Heering,&nbsp;Maria Kuzikov,&nbsp;Markus Wolf,&nbsp;Jeanette Reinshagen,&nbsp;Markus A. Queisser,&nbsp;Philip Gribbon,&nbsp;Andrea Zaliani,&nbsp;Ole Pless and Aimo Kannt,&nbsp;","doi":"10.1021/acsptsci.5c00195","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00195","url":null,"abstract":"<p >Targeted protein degradation (TPD) mediated by molecular glues is an innovative pharmaceutical paradigm. By binding to and modulating the surface of an E3-ligase component, molecular glue degraders can facilitate the recruitment of a specific target protein (or vice versa) and ultimately invoke target degradation. This mode of action results in specific challenges for the development of rational discovery strategies, and complex hit validation workflows may be required to reliably eliminate compounds that elicit nonspecific effects. With the aim to guide screening efforts, we optimized two orthogonal cell-based, target-centric assays for degrader discovery: (1) a time-resolved FRET assay directly quantifying the levels of a target protein and its degradation (signal inhibition) and (2) an assay coupling TPD to cell growth (signal rescue). To enable a deeper understanding of the individual assays’ strengths and limitations, we compared their statistical performance as well as respective hit populations by screening a specifically designed collection of about 1000 compounds containing well-annotated reference compounds and known frequent hitters (FHs). We found that the signal rescue format reliably and specifically captured active target degraders while efficiently filtering out interfering or FH compounds. Importantly, this format achieved to retrieve lower potency hits, which might be desirable in order to confidently include as many diverse chemical starting points as possible at the start of a drug discovery project.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 8","pages":"2600–2611"},"PeriodicalIF":3.7,"publicationDate":"2025-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsptsci.5c00195","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144806573","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":"Exploring Phosphatase and Tensin Homologue Deleted on Chromosome Ten (PTEN) as a Potential Therapeutic Target for Cardiac Hypertrophy","authors":"Mansi Jha,&nbsp; and ,&nbsp;Lokesh Kumar Bhatt*,&nbsp;","doi":"10.1021/acsptsci.5c00084","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00084","url":null,"abstract":"<p >While cardiovascular diseases continue to be the foremost cause of death worldwide, heart failure constitutes a major segment responsible for these mortalities. Heart failure results from exhausted cardiac myocytes that lose the ability to pump blood effectively. Cardiac hypertrophy is a condition of the heart wherein the thickening of the cardiomyocytes leads to an abnormal enlargement of the myocardium. The PI3K/AKT/mTOR signaling pathway plays a pivotal role in the development of cardiac hypertrophy by regulating cell growth, proliferation, metabolism, and survival in cardiac myocytes. The phosphatase and tensin homologue deleted on chromosome ten (PTEN) is a membrane-bound lipid phosphatase that facilitates dephosphorylation of PIP3 to PIP2, thus preventing the hyperactivation of the PI3K/AKT/mTOR signaling pathway. Augmentation of PTEN expression and activity can hinder cardiac hypertrophy and mitigate the risk of heart failure. The present review discusses the role of PTEN in controlling unchecked cardiomyocyte proliferation and provides an account of the novel findings from current research on the noncoding RNAs and proteins interacting with PTEN. The review further discusses the pharmacological agents that restore PTEN expression and function and may emerge as effective therapeutics for the treatment of cardiac hypertrophy.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 8","pages":"2312–2336"},"PeriodicalIF":3.7,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144806552","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":"Hit-to-Lead Studies of Pyrazinylpiperazines against Visceral Leishmaniasis: Pharmacokinetic Profile and In Vivo Efficacy of Potent Compounds against Leishmania infantum","authors":"Thibault Joseph William Jacques Dit Lapierre,&nbsp;Mariza Gabriela Faleiro de Moura Lodi Cruz,&nbsp;Gisele Barbosa,&nbsp;Analu R. Costa,&nbsp;Miguel Angel Chávez-Fumagalli,&nbsp;Thamires Quadros Froes,&nbsp;Priscila Zonzini Ramos,&nbsp;Paula Derksen Macruz,&nbsp;Thalita Carolyne Souza Trindade,&nbsp;Eduardo Jorge Pilau,&nbsp;Patricia Sampaio Tavares Veras,&nbsp;Maria Cristina Nonato,&nbsp;Katlin B. Massirer,&nbsp;Leonardo L. G. Ferreira,&nbsp;Adriano D. Andricopulo,&nbsp;Lídia Moreira Lima,&nbsp;Silvane Maria Fonseca Murta* and Celso de Oliveira Rezende Júnior*,&nbsp;","doi":"10.1021/acsptsci.5c00318","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00318","url":null,"abstract":"<p >As part of the hit-to-lead optimization of antileishmanial pyrazinylpiperazines, the Absorption, Distribution, Metabolism, and Excretion (ADME) properties of the initial hit and five candidates for <i>in vivo</i> studies were assessed <i>in vitro</i>. These candidates, which displayed improved potency against <i>Leishmania infantum</i> (IC₅₀ &lt; 5 μM), were selected from an earlier structure–activity relationship study. Such assessment revealed that, except for the catechol derivative <b>6</b>, all derivatives exhibited an improved overall ADME profile in comparison to the initial hit. The <i>para</i>-hydroxyl analog <b>2</b> stood out as the most promising candidate, being the second most potent compound <i>in vitro</i> against the parasite and showing far superior metabolic stability (more than twice as stable as the initial hit) in mouse liver microsomes, together with a reasonable gastrointestinal absorption and a lack of blood–brain barrier permeation. <i>In vivo</i> assessment of the antileishmanial efficacy of <b>2</b> in a BALB/c mice model of visceral leishmaniasis revealed a reduction in parasitemia by 91.1 and 90.0% in the spleen and liver, respectively, after a 10 day treatment of infected animals with a 100 mg/kg daily dose of <b>2</b>, without any acute toxicity or death among mice treated with <b>2</b>. Flow cytometry demonstrated that the antileishmanial activity of <b>2</b> is linked to a cytostatic effect, marked by cell cycle arrest in the G0/G1 phase and enhanced production of reactive oxygen species. Subsequent <i>in silico</i> studies suggested that the activity of the novel antileishmanial pyrazinylpiperazine lead <b>2</b> could be due to the inhibition of a nonspecific serine/threonine protein kinase in <i>Leishmania infantum</i>; however, <i>in vitro</i> inhibition assays failed to identify a target for <b>2</b> among a set of kinases and other proteins.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 8","pages":"2736–2755"},"PeriodicalIF":3.7,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsptsci.5c00318","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144806636","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":"Oral Prodrug of a Novel Glutathione Surrogate Reverses Metabolic Dysregulation and Attenuates Neurodegenerative Process in Transgenic Alzheimer’s Mice","authors":"Swetha Pavani Rao,&nbsp;Aminat O. Imam-Fulani,&nbsp;Wei Xie,&nbsp;Samuel Phillip,&nbsp;Krishna Chennavajula,&nbsp;Kiran D. Bhilare,&nbsp;Erin B. Lind,&nbsp;Ying Zhang,&nbsp;Robert Vince,&nbsp;Michael K. Lee* and Swati S. More*,&nbsp;","doi":"10.1021/acsptsci.5c00031","DOIUrl":"10.1021/acsptsci.5c00031","url":null,"abstract":"<p >Glycation-induced oxidative stress underlies the numerous metabolic ravages of Alzheimer’s disease (AD). Reduced glutathione levels in AD lead to increased oxidative stress, including glycation-induced pathology. Previously, we showed that the accumulation of reactive 1,2-dicarbonyls such as methylglyoxal, the major precursor of nonenzymatic glycation products, was reduced by the increased function of GSH-dependent glyoxalase-1 enzyme in the brain. In this two-pronged study, we evaluate the therapeutic efficacy of an orally bioavailable prodrug of our lead glyoxalase substrate, pro-ψ-GSH, for the first time in a transgenic Alzheimer’s disease mouse model. This prodrug delivers pharmacodynamically relevant brain concentrations of ψ-GSH upon oral delivery. Chronic oral dosing of pro-ψ-GSH effectively reversed the cognitive decline observed in the APP/PS1 mouse model. The prodrug successfully mirrors the robust effects of the parent drug, i.e., reducing amyloid pathology, glycation stress, neuroinflammation, and the resultant neurodegeneration, in these mice. We also report the first metabolomics study of such a treatment that yields key biomarkers linked to the reversal of AD-related metabolic dysregulation. Collectively, this study demonstrates the neuroprotective effect of pro-ψ-GSH in a symptomatic preclinical model of AD and paves the way for further preclinical advancement of such therapeutics. Metabolomic signatures identified could prove beneficial in the development of treatment-specific, clinically translatable biomarkers.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 8","pages":"2448–2464"},"PeriodicalIF":3.7,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144733698","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":"Cardioprotective Potential of ApoE-Derived Peptide (ApoEFrag) in Myocardial Infarction in Rats: A Mechanistic Study","authors":"Sakeel Ahmed,&nbsp;Mohd Rihan,&nbsp;Abhay H. Pande and Shyam Sunder Sharma*,&nbsp;","doi":"10.1021/acsptsci.4c00759","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00759","url":null,"abstract":"<p >Cardiovascular diseases (CVDs) are the leading cause of death among non-communicable diseases globally. Myocardial infarction (MI) is one of the most significant CVDs resulting from acute or chronic myocardial ischemia, which can lead to irreversible damage. Despite the substantial burden posed by these conditions, specific treatments remain limited to symptomatic management. ApoEFrag has been shown to be protective in the CNS. However, the cardioprotective potential of ApoE-mimetic has not been investigated. Thus, this study investigates the cardioprotective potential of ApoEFrag, a novel ApoE-mimetic peptide, in an acute MI model in rats. MI was induced in rats through two doses of isoproterenol (100 mg/kg via subcutaneous injection) administered 24 h apart. ApoEFrag was given at doses of 0.5 and 1 mg/kg to ISO-treated rats. Following treatment, we measured electrocardiogram (ECG) changes and arterial and ventricular pressure functions using the PV-loop system. Plasma and heart samples were collected for biochemical assessments, including plasma injury markers, hypertrophic index parameters, inflammatory markers, gene/protein expression analysis, and histopathological studies. ISO-induced MI resulted in alterations in ECG patterns, ventricular dysfunction, increased fibrosis, and elevated hypertrophic index parameters. Additionally, ISO administration led to increased inflammatory markers and oxidative stress levels, which were reversed by the ApoEFrag treatment. Furthermore, ApoEFrag significantly ameliorated cardiac injury, inflammation, hypertrophic index parameters, ECG alterations, ventricular dysfunction, and cardiac fibrosis in ISO-induced MI models. Notably, ApoEFrag also improved mitochondrial health. This study suggests that ApoEFrag has significant cardioprotective potential in an acute myocardial infarction model.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 8","pages":"2431–2447"},"PeriodicalIF":3.7,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144806565","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":"Applying the EU Regulatory Framework to Determine the Benefit–Risk Profile of Psychedelics","authors":"Kate Browne*,&nbsp;Ewa Bałkowiec-Iskra,&nbsp;Andre Elferink,&nbsp;Marion Haberkamp,&nbsp;Sabine Straus,&nbsp;Bruno Sepodes,&nbsp;Francisca Silva,&nbsp;Florence Butlen-Ducuing,&nbsp;Jarno Jansen,&nbsp;Ivana Silva,&nbsp;Pavel Balabanov,&nbsp;Juan Garcia Burgos and Steffen Thirstrup,&nbsp;","doi":"10.1021/acsptsci.5c00456","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00456","url":null,"abstract":"<p >Marketing authorization applications for psychedelics must align with the regulatory requirements and evidentiary standards required for the approval of all medicinal products in the European Union. While medicine regulators recognize the therapeutic potential of psychedelics, their characteristics present methodological challenges that complicate the design and interpretation of pivotal trials intended to assess their benefit–risk profile. This Viewpoint presents the European Medicines Agency’s perspective on the main knowledge gaps that must be addressed to ensure robust evidence generation for regulatory decision-making, as discussed at a multistakeholder workshop convened by the Agency in April 2024. Central among these are issues related to functional unblinding and expectancy and nocebo effects. Furthermore, characteristics of the trial population must be rigorously aligned with those defined in the therapeutic indication to ensure findings are relevant and generalizable. Development programmes should also support the characterization of the dose–response relationship, both in terms of pharmacological effects and the association between the subjective experience and therapeutic response. Moreover, the decision to incorporate either psychological support or psychotherapy in the therapeutic framework has methodological implications for the trial’s design and protocol, as well as the conditions for use, all of which require careful consideration. Additionally, characterization of the safety profile of psychedelics necessitates a multifaceted approach, including adequately powered clinical trials, the use of appropriate controls, the development of robust risk mitigation strategies, the establishment of continuous safety monitoring protocols, and the systematic consideration of ethical implications.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 8","pages":"2830–2838"},"PeriodicalIF":3.7,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsptsci.5c00456","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144806724","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}