Pharmacological Reviews最新文献

The extracellular accumulation of adenosine is a central mechanism of immune evasion within the tumor microenvironment. Elevated adenosine levels-driven by hypoxia, chronic inflammation, and upregulated ectonucleotidase activity, primarily through ectonucleoside triphophate diphosphoydrolase 1 and ecto-5'-nucleotidase-induce profound immunosuppression and promote tumor progression. In this setting, adenosine acts mainly through 2 G protein-coupled receptors, the adenosine A_2A receptor (A_2AAR) and the adenosine A_2B receptor (A_2BAR), which modulate diverse immune and stromal cell populations. A_2AAR signaling suppresses the effector activity of cytotoxic T lymphocytes and natural killer cells, whereas A_2BAR activation exerts broader effects by amplifying myeloid-derived immunosuppression, driving stromal remodeling, and fostering angiogenesis and metastatic dissemination. This review provides a comprehensive overview of the distinct and converging roles of A_2AAR and A_2BAR in immune, stromal, and tumor compartments. We critically analyze current strategies for developing selective and dual A_2AAR/A_2BAR antagonists, with a focus on structure-activity relationships, scaffold optimization, and pharmacokinetic profiling. In addition, we examine ongoing clinical trials and emerging combination therapies involving A_2AAR and A_2BAR antagonists in conjunction with immune checkpoint inhibitors, adoptive cell therapies, enzymatic axis blockade, radiotherapy, and classical chemotherapy. We also underscore the therapeutic potential of dual A_2AAR/A_2BAR antagonists as a multitarget approach to counteract overlapping immunosuppressive mechanisms. Overall, targeting the adenosine axis-particularly through dual receptor blockade-represents a promising strategy for reprograming the tumor microenvironment, reinvigorating antitumor immunity, and improving the efficacy of cancer immunotherapy. SIGNIFICANCE STATEMENT: Adenosine signaling via adenosine A_2A (A_2AAR) and A_2B (A_2BAR) receptors plays a central role in tumor-induced immunosuppression, limiting the efficacy of cancer immunotherapy. This review provides an integrated analysis of A_2AAR and A_2BAR functions across immune and stromal compartments, summarizes current selective antagonists (A_2AAR and A_2BAR) and dual antagonists, and highlights compounds in clinical studies. Moreover, it discusses synergistic combination strategies that integrate adenosine blockade with complementary immunotherapeutic and conventional approaches to enhance antitumor responses.

The endoplasmic reticulum (ER) is a dynamic membranous organelle that accounts for nearly half of the total membrane content in hepatocytes and serves as a central hub for protein folding and lipid biosynthesis. Given the liver's essential functions in protein production and secretion, lipid handling, and xenobiotic metabolism, hepatocyte ER homeostasis is essential for systemic metabolic control and health. Metabolic dysfunction-associated steatotic liver disease, which affects nearly 30% of the global population, is strongly linked to hepatic ER stress. Accumulating evidence highlights the unfolded protein response (UPR) as a key mechanistic regulator that integrates proteostasis and metabolic stress, thereby influencing disease progression from simple steatosis to inflammation-driven metabolic dysfunction-associated steatohepatitis (MASH). More recently, ER stress has also been implicated as a driver of MASH-related hepatocellular carcinoma, the most common primary liver cancer. In this review, we provide a comprehensive overview of the dynamic roles of the UPR and ER stress in hepatocytes, with particular emphasis on mechanistic insights derived from murine models of MASH-related hepatocellular carcinoma. We also summarize the current animal models of MASH that depend on hepatic ER stress. Finally, we discuss therapeutic candidates for MASH treatment, whose mechanisms of action involve ER stress and the UPR. SIGNIFICANCE STATEMENT: The endoplasmic reticulum (ER) functions as a central signaling hub, transmitting stress cues to transcriptional and translational programs through activation of the unfolded protein response, which orchestrates adaptive responses required for stress recovery. Given that hepatocytes are the largest cell population responsible for systemic protein distribution through ER-regulated protein synthesis, precise control of hepatic ER stress is essential not only for maintaining normal hepatocyte function but also for developing therapeutic strategies against ER stress-driven metabolic dysfunction-associated steatotic liver disease.

Before the Framingham Heart Study, the concept of cardiovascular disease (CVD) risk factors did not exist, and CVDs were seen as a consequence of aging. The first 2 reports in 1957 and 1961 identified high cholesterol levels as a major risk factor for CVD, highlighting the importance of lipid management to reduce CVD risk. Since then, the growing knowledge of CVD pathophysiology has led to the development of many drug classes to manage dyslipidemia and consequently, cardiovascular disease risk. Unfortunately, many of them, such as high-density lipoprotein-targeted or triglyceride-modulating drugs, have so far failed in clinical trials due to a lack of efficacy in cardiovascular disease protection or due to the appearance of side effects. Interestingly, low-density lipoprotein-targeted statin therapy revolutionized cardiovascular risk management and remains today the reference treatment in primary and secondary CVD prevention. In the last decades, novel low-density lipoprotein-targeted drugs, such as ezetimibe, proprotein convertase subtilisin/kexin type 9-targeted therapies, and bempedoic acid, have been approved by the Food and Drug Administration and have now found their place among the therapeutic arsenal of hypolipidemic drugs used in CVD risk management, in case of intolerance to statins or often in association with statins. This review focuses on the historical evolution of development strategies and on the successes and failures of lipid-lowering drugs to reduce cardiovascular disease risk, from the mid-20th century to the present, and concludes with novel challenging strategies in progress. SIGNIFICANCE STATEMENT: This review highlights the evolution of lipid-lowering therapies in atherosclerotic cardiovascular disease management, from statins to proprotein convertase subtilisin/kexin type 9 inhibitors. It underscores key successes, limitations, and emerging strategies, offering essential insights into their current and future roles in reducing atherosclerotic cardiovascular disease risk for a broad medical and scientific audience.

Globally, breast cancer (BC) remains the leading cause of cancer death in women. BC profoundly impacts the physical and psychological well being of millions of families worldwide and significantly burdens the healthcare system and the economy. Although chemotherapy remains a key component in BC treatment, its effectiveness is often limited by severe side effects and the development of drug resistance, highlighting the urgent need for innovative therapeutic strategies. One strategy to minimize side effects involves conjugating anticancer agents with tumor-targeting molecules such as antibodies, nanobodies, or peptides to enhance their selective delivery to cancer cells. The success of platinum-based drugs such as cisplatin and carboplatin has urged the exploration of other metal-based complexes as therapeutic agents for BC. Metals, including copper, zinc, and gold, are considered promising candidates for anticancer therapy because of their well established cytotoxic properties and relatively low cost. This review examines the use of metal-based agents conjugated to tumor-targeting molecules for the treatment of BC. Additionally, we propose a novel approach to conjugate innovative thiosemicarbazone-copper complexes with a targeting moiety, aiming to overcome 2 major clinical challenges of current anticancer drugs: side effects and drug resistance. SIGNIFICANCE STATEMENT: Metal-based drugs possess potent anticancer properties through diverse mechanisms. However, current agents like cisplatin face 2 major challenges common to most anticancer therapies: toxic side effects and drug resistance. One strategy to address these issues is the conjugation of anticancer agents to specific tumor-targeting moieties, such as antibodies, nanobodies, or peptides. To further limit resistance development, drug conjugates can be designed to include a potent, multitargeted payload, such as a thiosemicarbazone-copper complex that targets lysosomes.

Voltage-gated ion channels (VGICs) are critical regulators of membrane potential, cellular excitability, and calcium signaling in both excitable and nonexcitable tissues and constitute important drug targets for neurological, cardiovascular, and immunological diseases. This review describes recent progress in the pharmacology of voltage-gated Na⁺, voltage-gated Ca²⁺, and voltage-gated K⁺ channels, highlighting clinical-stage compounds, emerging therapeutic modalities, and new strategies in VGIC drug discovery, emphasizing the increasingly central role of protein structures and artificial intelligence. Several compounds targeting VGICs have progressed to clinical trials for epilepsy, atrial fibrillation, psoriasis, and difficult-to-treat disorders, such as chronic pain, schizophrenia, major depression, and amyotrophic lateral sclerosis. The therapeutic landscape for VGIC-related disorders is expanding beyond traditional small molecules and antisense oligonucleotides and gene therapies targeting VGICs at the mRNA or gene level are currently in both early and late clinical trial stages for Dravet syndrome and developmental epileptic encephalopathy. The progression of such varied modalities suggests that the extensive efforts dedicated to elucidating VGIC biophysics and structure, coupled with rigorous target validation, are beginning to translate into therapeutic advancements. Furthermore, we discuss emerging discovery strategies, including the growing impact of VGIC structures, computational structural modeling, virtual screening of focused and ultralarge libraries, and artificial intelligence-driven redesign and de novo design of biologics. Although these approaches are poised to substantially accelerate the early stages of ion channel drug discovery, the clinical stages will continue to require careful selection of indications and thoughtful clinical trial design to fully realize the long-held potential of VGICs as drug targets. SIGNIFICANCE STATEMENT: Drug development for voltage-gated ion channels is widely considered to be challenging. This article reviews recent advances in the pharmacology of voltage-gated Na⁺, voltage-gated Ca²⁺, and voltage-gated K⁺ channels by examining compounds currently in clinical trials, including emerging new therapeutic approaches such as antisense oligonucleotides and gene therapy. We then discuss noteworthy recent developments, including the increasing availability and impact of ion channel structures, structural modeling, virtual screening, and artificial intelligence-assisted protein design, which are likely to accelerate the early stages of ion channel drug discovery. Success of the later stages will continue to rely on rigorous target validation, and proper choices of clinical candidates and clinical trial design.

Evidence-based lipid-lowering therapies have significantly reduced, but not eradicated, atherosclerosis-induced cardiovascular disease, which remains a significant cause of morbidity and mortality around the world. This article focuses on precision medicine and examines the transformative potential of multiomics and machine learning in advancing theranostic approaches for atherosclerosis. The integration of multimodal data, known as multiomics, encompassing genomics and epigenomics, transcriptomics and epitranscriptomics, proteomics, metabolomics, and lipidomics, can support the comprehensive interrogation of molecular changes associated with disease initiation and progression. Machine learning algorithms are critical for identifying pertinent features of highly diverse and heterogeneous multiomic datasets. The combination of these new laboratory and data science technologies offers unprecedented opportunities for increasing precision in disease prediction, early detection, and monitoring, as well as more personalized treatments with current and new drugs. This article discusses the implications. It discusses their importance in the development and adoption of personalized medicine based on therapeutic approaches. SIGNIFICANCE STATEMENT: The review article explores new opportunities to develop and adopt theranostic strategies for atherosclerosis, derived from the integration of multiomics and machine learning to enhance personalized pharmacotherapy, precision prognostics, and diagnostics of atherosclerosis and atherosclerosis-derived cardiovascular diseases.

Administering drugs via inhalational routes is an attractive approach for treating respiratory diseases. Effective lung delivery provides a rapid therapeutic effect, minimizes systemic toxicities, and enhances overall public health responses, particularly for orally inhaled products during pandemics. However, assessing the pharmacokinetic (PK) properties of inhaled agents within the airway is challenging. In silico modeling, especially using physiologically based pharmacokinetic (PBPK) models, has emerged as a crucial clinical translational tool that integrates in vitro, in vivo, and ex vivo lung model data to improve predictions of lung exposure for inhaled drugs. Developing effective PBPK models requires a deeper understanding of the factors influencing drug disposition. Membrane transporters can significantly impact airway PKs, but there is a knowledge gap regarding their role and expression within the human airways. This review explores the following: (1) preclinical and clinical studies on lung transporter localization, expression, and their potential impact on the PKs of inhaled drugs; (2) conflicting data on transporter expression and localization; and (3) factors influencing transporter expression, such as inflammatory processes and diseases. We summarize the transporters involved in inhaled drug disposition, drug-specific parameters, and current PBPK models and approaches that account for transporter involvement. Only a few studies quantify transporter protein levels in the lung, particularly for respiratory diseases, limiting the ability to incorporate lung expression levels to inform the development of enhanced PBPK models. Overall, a comprehensive understanding of lung transporters and their impact on drug disposition is crucial for estimating and optimizing model-informed dosing of inhaled therapeutics. SIGNIFICANCE STATEMENT: Inhaled drugs are ideal for treating respiratory diseases because they increase drug exposure in the lungs and minimize off-target effects. Speeding up their approval, development, and dosing relies on accurate computational models. This review examines improving these models by integrating knowledge about lung transporters, focusing on understanding, characterizing, and quantifying these transporters and their influence on drug disposition.

Diabetes and related metabolic diseases have a high prevalence with increasing incidence and create a significant socioeconomic burden by their contribution to global mortality and disability-adjusted life years. According to data from the Global Burden of Disease Study, high fasting plasma glucose and high total cholesterol rank third and fourth in the list of global health risk factors, just behind high blood pressure and smoking. Diabetes adversely affects endothelial and cardiac function, thereby contributing significantly to the development and progression of cardiovascular diseases, which represents the leading health risk factors and causes of death worldwide. Oxidative stress and inflammation play a key role in the pathophysiology underlying diabetes mellitus and the associated cardiometabolic complications, such as metabolic dysfunction-associated fatty liver disease, hypertension, atherosclerosis, myocardial ischemia/reperfusion, and heart failure. Here, we highlight the beneficial effects of the modern antidiabetic drug classes of dipeptidyl peptidase 4 inhibitors, glucagon-like peptide 1 receptor agonists, and sodium-glucose cotransporter 2 inhibitors on overall and cardiovascular mortality of diabetic individuals, with particular emphasis on their effects on oxidative stress, inflammation, and endothelial dysfunction. We discuss the mechanisms of action and pleiotropic beneficial effects and compare them with standard diabetic and cardiovascular therapy. SIGNIFICANCE STATEMENT: Modern antidiabetic drugs confer organ protection that goes beyond simple glucose-lowering. SGLT2 inhibitors and incretin-based drugs possess direct reno-, vasculo-, and cardioprotective effects that are based on potent antioxidant and anti-inflammatory properties. Other pleiotropic effects comprise improved lipid handling and weight loss, prevention of thrombosis and ischemic heart damage, and beneficial regulation of nitric oxide signaling and epigenetic and microbiotic pathways.

Recent advancements in cell and tissue biology have fundamentally changed our understanding of cellular behavior, revealing that both stem and nonstem cells exhibit remarkable plasticity and adaptability. This discovery has paved the way for revolutionary medical drug therapies that leverage cell and tissue reprogramming to repair or regenerate damaged tissues, offering new hope for conditions that were once considered irreversible. Tissue reprogramming involves the activation of specific molecular pathways to convert the function of residual tissue to compensate for the loss of tissue function to aging, trauma, or disease processes. By targeting these pathways, emerging drugs can promote regenerative processes, enabling the restoration of tissue function lost due to aging, injury, or disease. These therapies have shown promising results in preclinical studies addressing a wide range of diseases. Unlike traditional treatments, which focus primarily on managing symptoms, tissue reprogramming therapies offer a dynamic approach that can fundamentally alter cellular states, leading to functional recovery. This review explores the current state of cell and tissue reprogramming, highlighting its potential applications in regenerative medicine and the challenges that must be addressed for successful clinical translation. As our understanding of cellular plasticity continues to evolve, these innovative therapies stand at the forefront of a new era in medicine, with the potential to transform treatment paradigms and significantly improve patient outcomes across a wide range of conditions. SIGNIFICANCE STATEMENT: Breakthrough technologies have transformed our understanding of cell and tissue biology, uncovering that cells and tissues possess remarkable adaptability and fluidity in their roles. This revelation has opened up exciting possibilities in regenerative medicine, where emerging drug therapies aim to harness and reprogram cells to repair or regenerate damaged tissues. An emerging class of medical drugs will activate the body's natural regenerative abilities, offering the potential to restore tissue function lost due to aging, injury, or disease.