Trends in pharmacological sciences最新文献

G protein-coupled receptors (GPCRs) constitute the largest family of membrane proteins and are involved in numerous physiological and pathological processes. Therapeutic antibodies targeting GPCRs, including monoclonal antibodies (mAbs), single-domain antibodies (sdAbs), and antibody-drug conjugates (ADCs), represent a promising class of biologics with high specificity and therapeutic potential. The integration of innovative screening technologies, structural biology, and computational approaches has significantly accelerated the discovery of antibody-based therapeutics against GPCRs. In this review, we discuss the emerging strategies used in the development of these therapeutic antibodies, examine key insights from pathogenic autoantibodies, evaluate the clinical trial landscape, and explore how emerging technologies such as artificial intelligence (AI)-assisted design and membrane-mimetic systems are driving the next generation of GPCR-targeted therapeutics.

Molecular glues (MGs) modulate protein interactions to inhibit, activate, or degrade targets. Classical MGs like thalidomide, cyclosporin, and fusicoccin were discovered serendipitously; a key challenge is to develop rational design approaches for MGs. Recent advances in knowledge of the structure-activity relationships (SAR) of MGs have resulted in rational design of new MGs. Moreover, newer structure-based design technologies have increased the target diversity of preclinical MGs and multiple candidates are in clinical trials. Here, we highlight the evolution of MGs from natural products to synthetic compounds and discuss integration of emerging technologies to inform their rational design into new therapeutic agents.

Bromodomain-containing protein 4 (BRD4) is a key transcriptional regulator in the bromodomain and extraterminal (BET) family. It promotes cancer and inflammation by binding to chromatin through its bromodomains. Although bromodomain inhibitors (e.g., BETi) show preclinical efficacy, their clinical application has been limited primarily by dose-limiting toxicities (DLTs), with resistance emerging as a secondary challenge. This motivates the development of strategies beyond conventional bromodomain inhibition. Here, we review emerging evidence that BRD4 sustains oncogenic programs through bromodomain-independent mechanisms, and discuss innovative approaches designed to overcome DLT. These include BRD4-targeted degraders, nonbromodomain ligands that disrupt scaffolding functions, post-translational modification (PTM) disruptors, and condensate modulators. We also discuss advances in chemically induced proximity (CIP) platforms that enable disease-state transcriptional reprogramming, and rational combination therapies (e.g., epigenetic-kinase inhibitors and BETi-immunotherapy integration) that minimize toxicity while addressing emerging resistance. Together, these approaches open new therapeutic frontiers for treating BRD4-driven diseases.

Chimeric antigen receptor (CAR)-based therapies are emerging for autoimmune diseases (ADs). Early-phase clinical studies in systemic lupus erythematosus (SLE) show encouraging results using autologous, allogeneic, and in vivo CAR T-cell (CAR-T) strategies. This forum compares these three strategies, highlighting clinical design, safety, and efficacy, and explores the translational challenges of in vivo CAR engineering in ADs.

Alzheimer's disease (AD) is an irreversible neurodegenerative disorder characterized by progressive cognitive decline and complex neuropathology. Its main features include amyloid-β (Aβ) plaques, tau neurofibrillary tangles (NFTs), and neuroinflammation. Current therapies provide only limited symptomatic relief and cannot stop disease progression, highlighting the urgent need for disease-modifying strategies. Recent research has revealed multiple roles of sirtuins in AD pathology, positioning them as promising therapeutic targets. Studies using small-molecule compounds to target sirtuins, in both cellular and animal models and clinical analyses of AD patients, demonstrate their therapeutic potential. This review discusses the distinct roles of individual sirtuin isoforms in AD pathogenesis and evaluates the therapeutic evidence for small-molecule sirtuin modulators.

Cancer cells exhibit unique metabolic reprogramming characterized by a significant increase in intracellular sodium ion levels. Sodium influences cancer cell metabolism, immune function, and drug resistance, and can trigger a unique cell death pathway when overloaded. Sodium-related transporters regulate cellular sodium ion levels and cancer progression. Targeting these transporters with specific inhibitors might therefore be an effective way to treat cancer. However, the precise relationship between sodium and cancer cell behavior is insufficiently studied and our understanding of the relevant transporters remains inadequate. In this review we summarize current understanding of the role of sodium in cancer. We analyze the impact of sodium-related transporters on cancer and current therapeutic strategies that target these transporters. We also highlight key challenges and discuss potential strategies for future investigations.

Dysregulated host immune responses are characteristic of a variety of inflammatory-mediated diseases. As such, novel immune-modulating therapies have been developed for the treatment of these inflammatory conditions. One condition that has seen a paradigm shift in therapeutic strategies is periodontal disease (PD), a common oral inflammatory condition. While initiated by bacteria, a dysregulated host immune response drives the disease. In this review, we discuss key innate and adaptive immune cells that have a role in PD progression, as well as different ways to target them. We highlight therapies that target dysregulated inflammatory pathways and their success in clinical trials. Lastly, we discuss the next steps for the clinical translation and subsequent adoption of these novel immunomodulatory treatments.

Small-conductance calcium-activated potassium (SK) channels regulate excitability and calcium signaling in neurons, cardiomyocytes, and endothelial cells. Their dysfunction contributes to a broad spectrum of disorders, including neurodegenerative diseases, mood disorders, cardiac arrhythmias, and cancer. Despite extensive study, the specific physiological roles and pathological contributions of the SK1-3 subtypes remain incompletely understood. Latest advances in structural biology, computational modeling, and pharmacology have clarified the mechanisms underlying SK channel gating, modulation, and dysfunction. In this review, we integrate these novel insights to link structural and functional diversity with physiological and disease processes. We further discuss how subtype-selective modulators are shaping precision strategies for therapeutic development.