Medicinal Research Reviews最新文献

{"title":"Molecular Glue Degraders in Early Development for Cancer Therapy.","authors":"E Sila Ozdemir, Hyunbum Jang, Ozlem Keskin, Attila Gursoy, Ruth Nussinov","doi":"10.1002/med.70104","DOIUrl":"https://doi.org/10.1002/med.70104","url":null,"abstract":"<p><p>Molecular glue degraders are an emerging class of small molecule allosteric modulators that induce or stabilize protein-protein interactions, enabling targeted degradation of previously intractable proteins. By redirecting E3 ligases to recognize neosubstrates, proteins that are not typically recognized by a specific E3 ubiquitin ligase, they expand the scope of drug discovery beyond traditional paradigms. We review mechanistic principles underlying molecular glue activity, including cooperativity, weak affinity interactions, structural degrons, and higher-order complex formation. We discuss discovery strategies, from serendipitous identification to emerging rational and chemoproteomic approaches, and key E3 ligase systems with relevance to oncology. We highlight clinical and preclinical applications, alongside challenges such as resistance mechanisms, context-dependent activity, and limitations in predicting neosubstrates. Molecular glues are transitioning from serendipitous discoveries to a mechanism-driven therapeutic platform. Progress depends on integrating structural biology, proteomics, and computational modeling to enable rational design and improve predictability. Expanding the repertoire of E3 ligases and understanding context-specific degradation will be critical to fully realize their potential in oncology and beyond.</p>","PeriodicalId":207,"journal":{"name":"Medicinal Research Reviews","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148899984","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AI-Driven Rational Design of Nanotherapeutics for Pancreatic Ductal Adenocarcinoma.","authors":"Seohyun Choo, Kaeun Chae, Jueun Lee, Inseon Kim, Seunghun S Lee","doi":"10.1002/med.70105","DOIUrl":"https://doi.org/10.1002/med.70105","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) remains a formidable malignancy characterized by late diagnosis, high recurrence rates, and pronounced chemoresistance. While nanoparticle-based drug delivery systems (NDDS) offer theoretical advantages over conventional therapies, their clinical translation in PDAC has been severely limited. The dense desmoplastic stroma, elevated interstitial fluid pressure, and hypovascularity effectively neutralize the enhanced permeability and retention (EPR) effect, restricting passive nanoparticle penetration. Consequently, the therapeutic paradigm is shifting from indiscriminate stromal depletion-which paradoxically accelerates metastasis-to stromal normalization and immune microenvironment reprogramming. This review comprehensively evaluates advanced NDDS platforms, highlighting transcytosis-triggering active targeting, stimuli-responsive carriers, and multimodal theranostic systems designed to bypass physical barriers and convert immunologically \"cold\" tumors to \"hot.\" Furthermore, we analyze the expanding role of artificial intelligence (AI) and machine learning in predicting synergistic drug combinations and optimizing nanoparticle physicochemical properties. Crucially, we critique current epistemic limitations in AI-driven nanomedicine, particularly data sparsity and the reliance on 2D preclinical models, emphasizing the necessity of 3D patient-derived organoid validation. By integrating rational NDDS design with AI and biomarker-driven strategies, this review maps the essential pathways toward personalized nanotherapeutics for PDAC.</p>","PeriodicalId":207,"journal":{"name":"Medicinal Research Reviews","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148890508","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glycolytic Reprogramming in Parkinson's Disease: From Bioenergetic Crosstalk to Therapeutic Modulation.","authors":"Ying Yi, Cen Chen, You He, Yu-Zhou Sun, Rui Cheng, Ming-Xuan Liu, Zhao-Guo Liu, Xiao-Ling Zhang","doi":"10.1002/med.70103","DOIUrl":"https://doi.org/10.1002/med.70103","url":null,"abstract":"<p><p>Parkinson's disease (PD) is increasingly recognized not merely as a localized proteinopathy, but as a systemic metabolic disorder driven by bioenergetic failure. While mitochondrial dysfunction is a well-established pathological hallmark, the compensatory reprogramming of glycolysis has emerged as a critical, yet double-edged, determinant of neuronal survival. This review critically examines the molecular and spatial architecture of glucose metabolism in the parkinsonian brain. We systematically dissect how upstream genetic regulators, including PTEN and PARK7/DJ-1, alongside downstream rate-limiting enzymes orchestrate the glycolytic shift in response to mitochondrial collapse and α-synuclein proteotoxicity. Moving beyond a neuron-centric view, we highlight cell-specific metabolic compartmentalization, emphasizing the disruption of the astrocyte-neuron lactate shuttle and the divergent glycolytic phenotypes of reactive microglia. Crucially, we evaluate the dual nature of glycolytic metabolites by demonstrating that a moderate flux sustains basal energy requirements and prevents apoptosis, whereas unchecked hyperglycolysis drives secondary pathological cascades through methylglyoxal-induced protein crosslinking and lactate-mediated neuroinflammation. By bridging these mechanistic insights with cross-disease metabolic links to type 2 diabetes and oncology, we evaluate the therapeutic potential of emerging metabolic modulators, including terazosin, cordycepin, and GLP-1 receptor agonists. Finally, we outline the pressing translational bottlenecks, particularly blood-brain barrier penetrance and cell-specific targeting, which must be overcome to successfully harness glycolytic modulation as a disease-modifying strategy for neurodegenerative disorders.</p>","PeriodicalId":207,"journal":{"name":"Medicinal Research Reviews","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148890481","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ferroptosis in Intestinal Diseases: Molecular Mechanisms, Therapeutic Potential, and Future Perspectives.","authors":"Liyan Deng, Kangdi Liu, Jiali Peng, Lianxiang Luo","doi":"10.1002/med.70099","DOIUrl":"https://doi.org/10.1002/med.70099","url":null,"abstract":"<p><p>Ferroptosis is an iron-driven, regulated form of cell death characterized by the gradual accumulation of lipid peroxides within the cell membrane. Intestinal diseases, including inflammatory bowel disease (IBD), ischemia-reperfusion injury (IRI), and colorectal cancer (CRC), are becoming increasingly prevalent and pose a significant burden on public health. Emerging evidence suggests that ferroptosis plays a context-dependent role in these conditions: inhibiting ferroptosis in normal intestinal epithelial cells can mitigate tissue damage, whereas inducing ferroptosis in malignant cells serves as a strategy to suppress tumor progression and metastasis. This review systematically integrates the latest insights into the molecular mechanisms regulating ferroptosis, the pathophysiology of various intestinal diseases, and translational therapeutic strategies. We highlight the therapeutic potential of targeting ferroptosis using inducers or inhibitors (often in combination with the gut microbiota, chemotherapy, radiotherapy, immunotherapy, and nanodrug delivery systems). Despite these advances, significant challenges remain, including the lack of standardized detection methods, variability across experimental models, drug-specific limitations, and safety concerns. In the future, the development of clinically relevant biomarkers, precise drug delivery platforms, and robust translational frameworks will be critical to realizing the potential of ferroptosis-targeted therapies. By integrating mechanistic, pathological, and therapeutic perspectives, this review provides a comprehensive roadmap for leveraging ferroptosis to manage intestinal diseases.</p>","PeriodicalId":207,"journal":{"name":"Medicinal Research Reviews","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148816824","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Developing the Dopamine D3 Receptor (D3R) Antagonist, (R)-VK4-116, as a Non-Opioid Medication for the Treatment of Opioid Use Disorder.","authors":"Chia-Kuei Wu, Yu-Chih Lin, Junfeng Huang, Bangwei Ding, Pramod Terse, Rahul Nandre, Haksong Jin, Molly Congdon, Kun Shen, Philip Sanderson, Gregory Tawa, Stephanie Mounaud, Marta De Santis, Donald Lo, Elizabeth A Ottinger, Amy Hauck Newman","doi":"10.1002/med.70101","DOIUrl":"10.1002/med.70101","url":null,"abstract":"<p><p>Opioid use disorder (OUD) remains a major global health challenge, and currently approved treatments (methadone, buprenorphine, and naltrexone) are all opioid receptor-targeting drugs with limitations in access, adherence, stigma, and use in polysubstance use disorders. Because the dopamine D3 receptor (D3R) is enriched in limbic brain regions involved in reward, drug dependence, and impulse control, it has become an attractive target for treating OUD and related substance use disorders. This review first surveys the emerging field of D3R antagonists as non-opioid therapeutics for substance use disorders, including D3R-selective compounds that have advanced into clinical development. We then present VK4-116 as a representative case study of translational progress in this field. Guided by D3R crystal structure-based modeling and medicinal chemistry optimization, VK4-116 was identified as a highly D3R-selective antagonist with favorable brain penetration and in vivo activity. In rodent models, VK4-116 reduced opioid self-administration, drug seeking, withdrawal-induced hyperalgesia, and irritability-like behavior, while enhancing opioid analgesia and reversing cocaine-induced cognitive deficits. The eutomer, (R)-VK4-116, was advanced through preclinical development, including scalable good manufacturing practices-compatible synthesis, formulation optimization to improve oral bioavailability, and investigational new drug-enabling toxicology studies defining toxicity endpoints, the no observed adverse effect level, and a safe clinical starting dose. Together, these findings support clinical evaluation of (R)-VK4-116 and illustrate the therapeutic promise of D3R antagonists for OUD and polysubstance use disorders.</p>","PeriodicalId":207,"journal":{"name":"Medicinal Research Reviews","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13598791/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148811560","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Application of Pyrrolidine in FDA-Approved Drugs.","authors":"Jiao Wang, Xiaolin Tan, Xiaoyan Wang, Yatao Wang, Hui Li, Zhong Yu, Qifang Liu","doi":"10.1002/med.70100","DOIUrl":"https://doi.org/10.1002/med.70100","url":null,"abstract":"<p><p>The saturated five-membered pyrrolidine ring is a privileged scaffold in medicinal chemistry. There is great interest in the pyrrolidine skeleton due to several key characteristics of this heterocyclic ring: its sp³ hybridized carbon framework, the contribution of multiple chiral centers, and the inherent planarization of the ring, typically manifested as conformational flexibility or pseudorotation. These characteristics make pyrrolidine-based structures highly attractive in the drug design for various biological targets. The pyrrolidine moiety also enhances drug-like properties such as metabolic stability, water solubility, and modulation of basicity, and can interact favorably with a wide range of biological targets through specific stereochemical interactions. This review surveys the synthesis and clinical applications of FDA-approved pyrrolidine-containing drugs since 2014, with the aim of informing the rational design of next-generation pyrrolidine-based therapeutics.</p>","PeriodicalId":207,"journal":{"name":"Medicinal Research Reviews","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148786196","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unraveling the Intricacies of G-Protein-Coupled Receptor Signaling in Cardiovascular Diseases: Novel Perspectives From Regulation to Therapeutic Targeting.","authors":"Shaherin Basith, Gwang Lee","doi":"10.1002/med.70087","DOIUrl":"https://doi.org/10.1002/med.70087","url":null,"abstract":"<p><p>G-protein-coupled receptors (GPCRs) represent a compelling intersection of structural biology, systems pharmacology, and clinical medicine. They function as essential molecular regulators of cardiovascular physiology, governing processes from the initiation of cardiac rhythm in the sinoatrial node to the regulation of vascular tone. Their widespread expression in cardiac and vascular tissues, combined with their ability to integrate diverse extracellular signals, positions GPCRs as key regulators of heart rate, contractility, vascular tone, inflammation, and metabolic homeostasis. Recent advances in GPCR structural biology, coupled with mechanistic insights into G-protein- and β-arrestin-mediated signaling mechanisms, underscore their central role in both cardiovascular health and disease. Notably, dysregulation of GPCR signaling has emerged as a unifying mechanism across major cardiovascular diseases (CVDs), contributing to pathological remodeling, impaired contractile function, and maladaptive vascular responses. This review uniquely integrates GPCR structural biology, signaling dynamics, and mechanosensitive and biased signaling mechanisms within the cardiovascular system. We discuss the contributions of class A, class B, and other GPCR families to cardiovascular physiology and pathology emphasizing their relevance to the development of targeted interventions for hypertension, heart failure, arrhythmias, atherosclerosis, and related CVDs. Together, these insights establish a contemporary framework for advancing precision GPCR-directed therapies in CVDs. By framing these developments within a mechanistic and translational context, the review offers a timely and clinically significant resource for both basic researchers and clinicians.</p>","PeriodicalId":207,"journal":{"name":"Medicinal Research Reviews","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148757026","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Boronic Acid Inhibitors of β-Lactamases: A Promising Strategy Against Antimicrobial Resistance.","authors":"Nicolò Santi, Federico Corsini, Robert A Bonomo, Emilia Caselli, Fabio Prati","doi":"10.1002/med.70097","DOIUrl":"https://doi.org/10.1002/med.70097","url":null,"abstract":"<p><p>The rise of antimicrobial resistance (AMR) poses a critical threat to global health, mostly due to the proliferation of β-lactamases, a class of enzymes responsible for the inactivation of β-lactam antibiotics. Among the most promising strategies to restore β-lactam efficacy is the use of β-lactamase inhibitors (BLIs), with boronic acid derivatives emerging as a pivotal and chemically versatile class. These compounds act as transition-state analogs, forming reversible covalent bonds with the catalytic serine of serine β-lactamases (SBLs), effectively mimicking the tetrahedral intermediate of β-lactam hydrolysis. Their electron-deficient boron atom, combined with a tunable scaffold, allows fine modulation of potency, selectivity, and pharmacokinetic properties. This review traces the evolution of boronic acid-based BLIs from early phenylboronic acids to next-generation acyclic and cyclic derivatives, highlighting key structure-activity relationships, binding mechanisms, and microbiological profiles. Clinically approved agents such as vaborbactam, as well as investigational compounds including taniborbactam, xeruborbactam, and benzoxaboroles, are discussed in the context of their therapeutic relevance and spectrum of activity. Particular attention is given to their ability to inhibit class A and C enzymes, with ongoing efforts aimed at extending coverage to class D and metallo-β-lactamases. Additionally, the review explores innovative approaches such as kinetic target-guided synthesis and fragment-based design to expand the chemical space of boronic acid pharmacophores. Together, these advances underscore the potential of boronic acid-based BLIs as powerful tools in overcoming β-lactamase-mediated resistance and developing next-generation antimicrobial therapies.</p>","PeriodicalId":207,"journal":{"name":"Medicinal Research Reviews","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148757326","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Artificial Intelligence-Driven Natural Product Drug Discovery: From Computational Genome Mining to Clinical Translation.","authors":"Antonio Lavecchia","doi":"10.1002/med.70098","DOIUrl":"https://doi.org/10.1002/med.70098","url":null,"abstract":"<p><p>Natural products (NPs) have historically yielded numerous therapeutic agents, yet their integration into modern drug discovery has been constrained by chemical complexity, low abundance, laborious dereplication, and limited target annotation. Convergence of multi-omics technologies with high-resolution structural and biological data has created unprecedented opportunities for artificial intelligence (AI) to accelerate NP-based therapeutics development. This review provides an operational, end-to-end workflow that explicitly connects computational predictions to medicinal chemistry decision points, addressing a critical gap between computational prediction and clinical translation. We trace the complete discovery pipeline: computational mining of biosynthetic gene clusters (BGCs) and metabolomes, deep learning (DL)-assisted structural elucidation and dereplication, network-based target identification using protein-ligand prediction, and generative molecular design inspired by NP scaffolds (including large language models, diffusion models, and genetic algorithms). Critical evaluation of current limitations (data scarcity, lack of standardized ontologies, model interpretability) is complemented by discussion of emergent strategies (foundation models trained on multi-modal data, graph neural networks, autonomous closed-loop laboratories). Representative case studies, including the synthetic AI-designed clinical benchmark rentosertib, illustrate the current evidence spectrum from discovery-level validation to early clinical benchmarking, while also highlighting that most AI-enabled NP discovery workflows remain at the preclinical or proof-of-concept stage, with limited quantitative evidence of improved clinical productivity. We conclude with an Outlook proposing feasible developments for 2025-2030: self-driving laboratories with reported acceleration in specific experimental contexts, foundation models enabling hypothesis-free chemical space exploration, and sustainability-aware AI frameworks embedding biodiversity impact assessments. This operational focus fills a critical gap between algorithmic capability and clinically actionable NP-derived leads. Importantly, while AI has demonstrably accelerated several early discovery steps, quantitative comparisons with classical NP workflows remain limited, and most reported advances are supported by preclinical or proof-of-concept studies rather than systematic evidence of improved time-to-lead, cost reduction, or clinical success rates.</p>","PeriodicalId":207,"journal":{"name":"Medicinal Research Reviews","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148682683","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Navigating the Complexity: A Comprehensive Review of GSK-3 Inhibition in Regenerative Medicine.","authors":"Davide Schiroli, Alessia Merra, Chiara Marraccini, Lucia Merolle, Graziella Pellegrini, Eleonora Maurizi","doi":"10.1002/med.70095","DOIUrl":"https://doi.org/10.1002/med.70095","url":null,"abstract":"<p><p>Glycogen synthase kinase-3 (GSK-3) is a central regulator of numerous cellular signaling pathways, with critical roles in metabolism, proliferation, differentiation, and tissue regeneration. This review explores the multifaceted effects of pharmacological GSK-3 inhibition across multiple body districts, focusing on its highly context-dependent impact. It has been proven that blocking GSK-3 promotes embryonic stem cell self-renewal, neuronal differentiation, osteogenesis, and dentinogenesis, while it has an inhibitory effect on adipogenesis. GSK-3 inhibition effects on muscle, heart, liver, and skin are more complex and often contradictory, influenced by critical factors, such as dosage, timing of administration, cellular microenvironment, and isoform specificity (GSK-3α vs. GSK-3β). A dual role also emerges in fibrosis and epithelial-mesenchymal transition processes, where GSK-3 inhibition can either have a suppressive or promoting role. Despite its promising therapeutic potential in regenerative medicine, clinical translation is still hindered by its contradictory effects in some tissues, the need for fine-tuned treatment regimens, and the lack of isoform-specific inhibitors. Selective targeting approaches and robust preclinical studies are thus essential to fully harness the therapeutic potential of GSK-3 modulation.</p>","PeriodicalId":207,"journal":{"name":"Medicinal Research Reviews","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148676342","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}