ACS Pharmacology and Translational Science最新文献

{"title":"Chemistry Outside the Flask: Redefining Selectivity In Vivo with Image Guidance","authors":"Erik Cressman*,&nbsp;Danielle Stolley,&nbsp;Natalie Fowlkes,&nbsp;Shubhneet Warar,&nbsp;Edd Felix,&nbsp;Waldemar Priebe,&nbsp;Steve Parrish and David Fuentes,&nbsp;","doi":"10.1021/acsptsci.4c0064910.1021/acsptsci.4c00649","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00649https://doi.org/10.1021/acsptsci.4c00649","url":null,"abstract":"<p >Fundamental to drug dosing and formulation strategies are the therapeutic index and maintaining a plasma concentration within a safe but therapeutic window. This holds true for oral, intravenous, transdermal, and intramuscular delivery methods. A key factor in plasma concentration is the half-life for any drug, because this affects the appropriate dose. Drugs with a very short half-life pose a particular challenge. Therefore, highly reactive compounds are not generally used for therapeutic purposes. However, targeted delivery under direct visualization, combined with cessation of blood flow in the area, could potentially allow the use of these highly reactive compounds. Such a strategy requires that little or none of the material reach systemic circulation to cause off-target toxicities. If this approach were applied to cancer, multiple mechanisms could be activated to disrupt cellular metabolism. We report our experience in a swine model using a strong electrophile, dichloroacetyl chloride, dissolved in a hydrophobic vehicle and delivered to the liver with high spatial selectivity using a microcatheter. Compared with positive controls, very little of the reaction product, dichloroacetate, a known inhibitor of pyruvate dehydrogenase kinase, was detected in plasma over 4 h. We further demonstrated persistence of the material for 24 h with highly localized and well-defined coagulative necrosis in the target vascular bed, without evidence of dose-limiting toxicity over the duration of the experiment.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 4","pages":"1087–1095 1087–1095"},"PeriodicalIF":4.9,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsptsci.4c00649","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143814429","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":"Propofol: Current Updates, Challenges, and Strategies for Improved Self-Nanoemulsifying Formulation","authors":"Mohsin Kazi*,&nbsp;Ali Gaskari,&nbsp;Ahmad A. Shahba,&nbsp;Shoaib Ahmad,&nbsp;Mohammed S. Aldughaim and Muhammad Delwar Hussain*,&nbsp;","doi":"10.1021/acsptsci.4c0074510.1021/acsptsci.4c00745","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00745https://doi.org/10.1021/acsptsci.4c00745","url":null,"abstract":"<p >Propofol, commonly used as an intravenous (IV) anesthetic and sedative, requires strict aseptic handling to prevent microbial contamination. There have been alarming reports of bloodborne pathogen transmission due to unsafe injection practices and the reuse of single-use propofol vials. Additionally, managing pain during anesthesia induction and determining the correct dose for sedation pose significant challenges with IV propofol. Despite its effectiveness, propofol’s limited water solubility and poor oral bioavailability restrict its use outside of anesthesia. Understanding how propofol works remains complex. Advances in nanotechnology have significantly improved the bioavailability of hydrophobic drugs through self-nanoemulsifying drug delivery systems (SNEDDS). These lipid-based formulations create nanoscale emulsions upon contact with gastrointestinal fluids, enhancing drug solubilization and absorption. For instance, studies have shown that SNEDDS can improve bioavailability by 2- to 3-fold compared to traditional formulations, as demonstrated with drugs such as propofol, whose poor water solubility limits its therapeutic efficiency. This review delves into propofol’s chemical properties, pharmacokinetics, and pharmacodynamics, evaluating the potential of SNEDDS to address its formulation challenges and discussing promising candidates in clinical trials. Furthermore, it examines the potential of using SNEDDS to improve propofol’s bioavailability through nonintravenous routes. This review highlights the potential of SNEDDS to enhance propofol’s therapeutic effectiveness beyond its traditional use in anesthesia, opening new avenues for its application.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 4","pages":"1013–1027 1013–1027"},"PeriodicalIF":4.9,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143818925","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":"Recommended Tool Compounds: Thienotriazolodiazepines-Derivatized Chemical Probes to Target BET Bromodomains","authors":"Chuhui Huang,&nbsp;Kate S. Harris,&nbsp;Ghizal Siddiqui and Manuela Jörg*,&nbsp;","doi":"10.1021/acsptsci.4c0072610.1021/acsptsci.4c00726","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00726https://doi.org/10.1021/acsptsci.4c00726","url":null,"abstract":"<p >Thienotriazolodiazepines, including (+)-JQ1 (<b>4</b>), are well-known inhibitors of the bromodomain (BD) and extra-terminal domain (BET) family of proteins. Despite the suboptimal physicochemical properties as a drug candidate, such as poor solubility and half-life, (+)-JQ1 (<b>4</b>) has proven as an effective chemical probe with high target potency and selectivity. (+)-JQ1 (<b>4</b>) and (+)-JQ1-derived chemical probes have played a vital role in chemical biology and drug discovery over the past decade, which is demonstrated by the high number of impactful research studies published since the disclosure of (+)-JQ1 (<b>4)</b> in 2010. In this review, we discuss the development of (+)-JQ1-derivatized chemical probes over the past decade and their significant contribution to scientific research. Specifically, we will summarize the development of innovative label-free and labeled (+)-JQ1-derivatized chemical probes, such as bivalent, covalent, and photoaffinity probes as well as protein degraders, with a focus on the design of these chemical probes.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 4","pages":"978–1012 978–1012"},"PeriodicalIF":4.9,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsptsci.4c00726","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143814727","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":"Comparative Evaluation and Profiling of Chemical Tools for the Nuclear Hormone Receptor Family 2.","authors":"Max Lewandowski, Romy Busch, Julian A Marschner, Daniel Merk","doi":"10.1021/acsptsci.4c00719","DOIUrl":"10.1021/acsptsci.4c00719","url":null,"abstract":"<p><p>Nuclear receptors regulate transcription in response to ligand signals and enable the pharmacological control of gene expression. However, many nuclear receptors are still poorly explored and are not accessible to ligand-based target identification studies. In particular, most members of the NR2 family are among the least studied proteins of the class, and apart from the retinoid X receptors (RXR), validated NR2 ligands are very rare. Here, we gathered the NR2 modulators reported in literature for comparative profiling in uniform test systems. Most candidate compounds displayed insufficient on-target activity or selectivity to be used as chemical tools for NR2 receptors underscoring the urgent need for further NR2 ligand development. Nevertheless, a small NR2 modulator set could be assembled for application in a chemogenomic fashion. There are 48 ligand-activated transcription factors in humans forming the superfamily of nuclear receptors (NRs, Figure 1a),^1,2 which translate (endogenous) ligand signals into changes in gene expression patterns.³ The multifaceted roles of NRs span pivotal physiological processes, encompassing metabolism, inflammation, and cellular differentiation.⁴ Over decades, the NR1 and NR3 receptor families, including (steroid) hormone receptors and lipid sensors, have emerged as well-explored therapeutic targets of essential drugs like, for example, glucocorticoids as anti-inflammatory drugs, estrogen receptor modulators as contraceptives and anticancer agents, and PPAR agonists as oral antidiabetics.^5-7 Despite this progress, a significant portion of the NR superfamily remains understudied, particularly within the NR2 family which comprises the hepatocyte nuclear factor-4 receptors (HNF4α/γ; NR2A1/2), the retinoid X receptors (RXRα/β/γ; NR2B1-3), the testicular receptors (TR2/4; NR2C1/2), the tailless-like receptors (TLX and PNR; NR2E1/3), and the COUP-TF-like receptors (COUP-TF1/2, V-erBA-related gene; NR2F1/2/6).^8,9 Apart from RXR, all NR2 receptors are considered as orphan, and their ligands remain widely elusive. Therefore, chemical tools for most NR2 receptors are rare and poorly annotated posing an obstacle to target identification and validation studies. To enable chemogenomics on NR2 receptors and improve annotation, of the few available ligands, we gathered a scarce collection of NR2 modulators (agonists, antagonists, inverse agonists) for comparative evaluation and profiling. While the NR2B family (RXR) is well covered with high-quality ligands and a few early tools are available for NR2E1, we found the available ligands of the NR2A and NR2C families of insufficient quality to be used as chemical tools.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":" ","pages":"854-870"},"PeriodicalIF":4.9,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7617459/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143568431","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":"Schwann Cell Protein Kinase RNA-like ER Kinase (PERK) Is Not Necessary for the Development of Diabetic Peripheral Neuropathy but Negates the Efficacy of Cemdomespib Therapy","authors":"Sugandha Patel,&nbsp; and ,&nbsp;Rick T. Dobrowsky*,&nbsp;","doi":"10.1021/acsptsci.5c0002110.1021/acsptsci.5c00021","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00021https://doi.org/10.1021/acsptsci.5c00021","url":null,"abstract":"<p >Diabetic peripheral neuropathy (DPN) is a common complication of diabetes arising in part from glycemic damage to neurons and Schwann cells (SC). While the pathogenic mechanisms of DPN are complex, mitochondrial dysfunction and endoplasmic reticulum (ER) stress contribute to the development of DPN and serve as therapeutic targets for disease modification. Cemdomespib is an orally bioavailable small molecule which alleviates clinical indices of DPN that correlate with improvements in neuronal oxidative stress and mitochondrial bioenergetics. However, the contribution of SC ER stress in the onset of DPN and the therapeutic efficacy of cemdomespib remains unknown. To address this issue, mice expressing a conditional deletion of protein kinase RNA-like ER kinase (PERK) in myelinating SCs (SC-cPERK KO) and control SC-PERK^f/f mice were rendered diabetic with streptozotocin. Diabetic SC-PERK^f/f and SC-cPERK KO mice developed a similar magnitude of DPN as quantified by the onset of a thermal/mechanical hypoalgesia, decreases in nerve conduction velocity (NCV) and intraepidermal fiber density (iENFD). After 8 weeks of diabetes, daily treatment with 1 mg/kg cemdomespib for an additional 8 weeks significantly improved thermal/mechanical hypoalgesia, NCV, iENFD and decreased markers of ER stress in diabetic SC-PERK^f/f mice, but the drug had no effect in diabetic SC-cPERK KO mice. Nrf2 is a PERK substrate and studies using rat SCs subjected to ER stress demonstrated that cemdomespib increased Nrf2 activity. Collectively, these data suggest that activation of SC PERK by diabetes is not necessary for the onset of DPN, but serves as a target in the action of cemdomespib, potentially by increasing Nrf2 activity.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 4","pages":"1129–1139 1129–1139"},"PeriodicalIF":4.9,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143814482","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":"Engineered Metal–Organic Frameworks for Targeted CRISPR/Cas9 Gene Editing","authors":"Navid Rabiee*,&nbsp; and ,&nbsp;Mohammad Rabiee*,&nbsp;","doi":"10.1021/acsptsci.5c0004710.1021/acsptsci.5c00047","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00047https://doi.org/10.1021/acsptsci.5c00047","url":null,"abstract":"<p >The development of precise and efficient delivery systems is pivotal for advancing CRISPR/Cas9 gene-editing technologies, particularly for therapeutic applications. Engineered metal–organic frameworks (MOFs) have emerged as a promising class of inorganic nonviral vectors, offering unique advantages such as tunable porosity, high cargo-loading capacity, and biocompatibility. This review explores the design and application of MOF-based nanoplatforms tailored for the targeted delivery of CRISPR/Cas9 components, aiming to enhance gene-editing precision and efficiency. By incorporating stimuli-responsive linkers and bioactive ligands, these MOFs enable controlled release of CRISPR/Cas9 payloads at the target site. Comparative discussions demonstrate superior performance of MOFs over conventional nonviral systems in terms of stability, transfection efficiency, and reduced off-target effects. Additionally, the intracellular trafficking mechanisms and the therapeutic potential of these platforms in preclinical models are discussed. These findings highlight the transformative potential of MOF-based delivery systems in overcoming the challenges associated with gene-editing technologies, such as immunogenicity and cytotoxicity, paving the way for their application in precision medicine. This review provides a blueprint for the integration of nanotechnology and genome editing, advancing the frontier of nonviral therapeutic delivery systems.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 4","pages":"1028–1049 1028–1049"},"PeriodicalIF":4.9,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143814619","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":"In Vivo and In Vitro Pharmacokinetic Studies of a Dual Topoisomerase I/II Inhibitor","authors":"Jonas Hildebrandt,&nbsp;Dirk O. Bauerschlag,&nbsp;Gert Fricker,&nbsp;Ulrich Girreser,&nbsp;Björn Konukiewitz,&nbsp;Franziska Kellers,&nbsp;Nicolai Maass,&nbsp;Bernd Clement* and Inken Flörkemeier*,&nbsp;","doi":"10.1021/acsptsci.4c0059610.1021/acsptsci.4c00596","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00596https://doi.org/10.1021/acsptsci.4c00596","url":null,"abstract":"<p >Due to high mortality rates, new and more effective drugs are urgently needed in cancer therapy. The novel dual topoisomerase inhibitor P8-D6, a dimethylaminoethyl-substituted pyridophenanthroline, showed <i>in vitro</i> impressive induction of apoptosis in tumors such as ovarian cancer or multiple myeloma compared to the current standard therapy. The purpose of this study was to investigate its <i>in vitro</i> and <i>in vivo</i> pharmacokinetics and to discover further potential drug candidates. Samples of plasma, various tissues, urine, feces, and cell culture supernatants were examined by HPLC. In addition, the efficacy of the metabolites against ovarian cancer was determined <i>in vitro</i>. Three phase I metabolites were identified <i>in vitro</i> and <i>in vivo</i>, and one phase II metabolite was identified <i>in vivo</i>. Among the metabolites, <i>N</i>-dealkylated P8-D6 (P8-D6 mono) achieved efficacy similar to that of P8-D6 in ovarian cancer. P8-D6 showed a relevant inhibitory effect on the efflux pumps P-GP (IC₅₀ = 20.63 μM) and BCRP (16.32 μM). The calculated oral bioavailability in Sprague–Dawley rats was 21.5%, while P8-D6 had a high plasma protein binding of 99% and an extensive tissue distribution with an apparent volume of distribution between 57.69 (i.v.) and 82.92 (p.o.) L/m². Both P8-D6 and its metabolites were detected in urine and feces. This study provides a basis for the clinical application of P8-D6 and has also identified P8-D6 mono as a very potent and metabolically stable drug candidate.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 4","pages":"1050–1071 1050–1071"},"PeriodicalIF":4.9,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsptsci.4c00596","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143814493","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":"Comprehensive Characterization of Bruton’s Tyrosine Kinase Inhibitor Specificity, Potency, and Biological Effects: Insights into Covalent and Noncovalent Mechanistic Signatures","authors":"Antonia C. Darragh,&nbsp;Andrew M. Hanna,&nbsp;Justin H. Lipner,&nbsp;Alastair J. King,&nbsp;Nicole B. Servant and Mirza Jahic*,&nbsp;","doi":"10.1021/acsptsci.4c0054010.1021/acsptsci.4c00540","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00540https://doi.org/10.1021/acsptsci.4c00540","url":null,"abstract":"<p >Uncovering a drug’s mechanism of action and possible adverse effects are critical components in drug discovery and development. Moreover, it provides evidence for why some drugs prove more effective than others and how to design better drugs altogether. Here, we demonstrate the utility of a high-throughput <i>in vitro</i> screening platform along with a comprehensive panel to aid in the characterization of 15 Bruton’s tyrosine kinase (BTK) inhibitors that are either approved by the FDA or presently under clinical evaluation. To compare the potency of these drugs, we measured the binding affinity of each to wild-type BTK as well as a clinically relevant resistance mutant of BTK (BTK C481S). In doing so, we discovered a considerable difference in the selectivity and potency of these BTK inhibitors to the wild-type and mutant proteins. Some of this potentially contributes to the adverse effects experienced by patients undergoing therapy using these drugs. Overall, noncovalent BTK inhibitors showed stronger potency for both the wild-type and mutant BTK when compared with that of covalent inhibitors, with the majority demonstrating a higher specificity and less off-target modulation. Additionally, we compared biological outcomes for four of these inhibitors in human cell-based models. As expected, we found different phenotypic profiles for each inhibitor. However, the two noncovalent inhibitors had fewer off-target biological effects when compared with the two covalent inhibitors. This and similar in-depth preclinical characterization of drug candidates can provide critical insights into the efficacy and mechanism of action of a compound that may affect its safety in a clinical setting.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 4","pages":"917–931 917–931"},"PeriodicalIF":4.9,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsptsci.4c00540","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143814476","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":"Psychedelics and Eating Disorders: Exploring the Therapeutic Potential for Anorexia Nervosa and Beyond","authors":"Shuai Hu,&nbsp;Cong Lin,&nbsp;Hongshuang Wang* and Xiaohui Wang*,&nbsp;","doi":"10.1021/acsptsci.5c0009410.1021/acsptsci.5c00094","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00094https://doi.org/10.1021/acsptsci.5c00094","url":null,"abstract":"<p >Anorexia nervosa (AN) is a severe psychiatric disorder characterized by extreme food restriction, an intense fear of weight gain, and a distorted body image, leading to significant morbidity and mortality. Conventional treatments such as cognitive-behavioral therapy (CBT) and pharmacotherapy often prove inadequate, especially in severe cases, highlighting the need for novel therapeutic approaches. Recent research into psychedelics, such as psilocybin and 3,4-methylenedioxymethamphetamine (MDMA), offers promising avenues for treating anorexia nervosa by targeting its neurobiological and psychological underpinnings. These psychedelics disrupt maladaptive neural circuits, enhance cognitive flexibility, and facilitate emotional processing, offering potential relief for patients unresponsive to traditional therapies. Early studies have shown positive outcomes with psychedelics, including reductions in anorexia nervosa symptoms and improvements in psychological well-being. However, further research is needed to establish their long-term safety, efficacy, and integration into clinical practice. Addressing the legal, ethical, and safety challenges will be crucial in determining whether psychedelics can transform the treatment landscape for anorexia nervosa and other eating disorders.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 4","pages":"910–916 910–916"},"PeriodicalIF":4.9,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143814679","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":"Recent Advances in the Development of Sigma Receptor (Radio)Ligands and Their Application in Tumors","authors":"Tao Wang*,&nbsp;Na Sun,&nbsp;Yanxi Ma and Song Zhang*,&nbsp;","doi":"10.1021/acsptsci.4c0071110.1021/acsptsci.4c00711","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00711https://doi.org/10.1021/acsptsci.4c00711","url":null,"abstract":"<p >Cancer ranks among the top triumvirate leading causes of human deaths worldwide. The pathological mechanisms are notably intricate, demonstrating proliferative and metastatic capabilities, which complicate therapeutic interventions. The sigma-1 receptor (σ₁R) plays a crucial role in tumor survival and migration, while the sigma-2 receptor (σ₂R) is intimately associated with tumor proliferation. This review encapsulated the investigation concerning σ₁R and σ₂R in neoplasms and rigorously summarized the ligands and radio-ligands development and their tumor applications, such as antitumor cell proliferation and PET/SPECT imaging in tumors. A comprehensive classification discussion was undertaken regarding the chemical structures and emphasized the possibility of dual/multitargeted ligands. Ultimately, we discussed the effects of chiral structures and the pharmacological characteristics of ligands on affinity and pharmacokinetic features <i>in vivo</i>, particularly concerning radiopharmaceuticals. This review functions as a beneficial resource, fostering ligand deployment and stimulating the generation of innovative ideas for developing innovative radiopharmaceuticals.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 4","pages":"951–977 951–977"},"PeriodicalIF":4.9,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143814675","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}