Trends in pharmacological sciences最新文献

G protein-coupled receptors (GPCRs) are a large superfamily of receptors critical for mammalian cell-cell communication and a common drug target. A new study has revealed that the human gut microbiome can metabolize GPCR-targeted drugs into both expected and surprising metabolites, with potentially broad implications for the treatment of disease.

Pulmonary arterial hypertension (PAH) is a progressive, life-threatening vasculopathy characterized by sustained vasoconstriction and pathological remodeling of small pulmonary arteries. While current vasodilator therapies improve symptoms and survival, they are not curative and fail to reverse vascular remodeling. Recently, a shift toward disease-modifying strategies has emerged, driven by preclinical advances now entering clinical translation. The approval of sotatercept, the first agent presumed to target vascular remodeling, and the development of seralutinib, an inhaled tyrosine kinase inhibitor (TKI), mark key milestones. In this review, we focus on anti-remodeling therapies that have progressed from preclinical models to clinical trials. These include agents targeting cell cycle regulators, kinase pathways, epigenetic modifiers, bone morphogenetic protein receptor type 2 (BMPR2) signaling, and senescence in pulmonary arterial smooth muscle cells (PASMCs), offering renewed hope for durable PAH treatment.

The orphan G protein-coupled receptor (GPCR) GPR17, whose physiological agonist remains unknown, has emerged as a promising drug target for multiple sclerosis (MS). Blockade of the receptor enables remyelination and may offer a novel therapeutic strategy for MS. Only recently, potent and selective tool compounds for GPR17 have become available, and patents on antagonists have surged, leading to the first clinical candidate, the GPR17 antagonist PTD802, which is to be developed for MS therapy. This may pave the way for further clinical studies exploring additional indications, such as neurodegenerative diseases. The newly determined cryo-electron microscopy (cryo-EM) structure of GPR17 is expected to facilitate future structure-based drug design efforts. This review presents and discusses these latest developments, providing a timely and comprehensive overview to guide future research in the field.

Lymphocyte activation gene-3 (LAG-3) has emerged as a critical immune checkpoint receptor primarily modulating T-cell responses through distinct immune regulatory mechanisms. Recent advances have elucidated LAG-3's complex receptor-ligand interactions, structure-function relationships, and unique signaling pathways. LAG-3 antagonistic antibodies, such as relatlimab approved for melanoma, have shown promising efficacy with favorable toxicity profiles, though only in combinational therapies. While LAG-3's role in oncology continues to expand, it is also gaining recognition as a potential therapeutic target for other disorders. This review highlights recent progress in understanding LAG-3's molecular features, ligand regulation, signaling, and immune modulation mechanisms. Additionally, it explores emerging questions in oncology and the exciting potential of therapies targeting the LAG-3 pathway in autoimmune disease. A deeper understanding of LAG-3's confounding biology and disease relevance would drive the development of novel immunotherapies across broader clinical indications.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease, and often progresses to hepatic fibrosis, cirrhosis, and liver failure. Despite its increasing prevalence, effective pharmacological treatments for MASLD-related fibrosis remain limited. Recent research has highlighted AMP-activated protein kinase (AMPK) as a key regulator of the processes that promote fibrogenesis, and AMPK activation shows potential in mitigating fibrosis. Advances in AMPK activators and deeper insights into their role in fibrotic pathways have recently revitalized interest in targeting AMPK for fibrosis treatment. This review discusses the molecular mechanisms linking AMPK to hepatic fibrosis and evaluates emerging AMPK-directed therapies. Furthermore, it addresses challenges in clinical translation. Importantly, we combine the latest mechanistic discoveries with recent therapeutic developments to provide a comprehensive perspective on AMPK as a target for hepatic fibrosis treatment.

Regulatory agencies require comprehensive toxicity testing for prenatal drug exposure, including new drugs in development, to reduce concerns about developmental toxicity, that is, drug-induced toxicity and adverse effects in pregnant women and fetuses. However, defining developmental toxicity endpoints and optimal analysis of associated public big data remain challenging. Recently, artificial intelligence (AI) approaches have had a critical role in analyzing complex, high-dimensional data, uncovering subtle relationships between chemical exposures and associated developmental risks. Here, we present an overview of major big data resources and data-driven models that focus on predicting various toxicity endpoints. We also highlight emerging, interpretable AI models that integrate multimodal data and domain knowledge to reveal toxic mechanisms underlying complex endpoints, and outline a potential framework that leverages multiple interpretable models to comprehensively evaluate chemical-induced developmental toxicity.

Antibody-drug conjugates (ADCs) have revolutionized oncology by enabling the delivery of cytotoxic agents. However, persistent limitations in payload diversity and emerging drug-resistance mechanisms have spurred investigations into innovative payload modalities. Molecular glue-antibody conjugates (MACs), which utilize molecular glues as payloads, represent a groundbreaking advance in this field. By leveraging the catalytic, event-driven nature of molecular glues, MACs offer enhanced efficacy, reduced off-target effects, and an improved therapeutic index. Two MACs are now in clinical trials. This review explores MAC mechanisms, advances, and potential to surpass traditional ADCs and molecular glues, while addressing development challenges and future directions.

Fungal infections are increasing globally, with limited antifungal classes, drug toxicity issues, and the rapid emergence of multidrug resistance (MDR). By using a glycosyltransferase phylogeny-guided strategy, Deng and colleagues recently identified a new broad-spectrum polyene macrolide active against many fungal pathogens, with a novel mechanism of action and excellent safety profile.

Efferocytosis, the clearance of apoptotic cells (ACs) by phagocytes, is crucial for bone homeostasis and immune balance. This tightly regulated process depends on molecular markers such as phosphatidylserine on ACs and MERTK on phagocytes. In the bone microenvironment, multiple cell types participate in efferocytosis, including osteal macrophages, mesenchymal stem cells, osteoblasts, and osteoclasts, directly influencing bone remodeling and immune responses. Impaired efferocytosis disrupts bone turnover, exacerbates inflammation, and contributes to inflammatory bone diseases. Despite its recognized importance, the precise mechanisms regulating efferocytosis in osteoimmunology remain underexplored, including specific signaling pathways, cell-specific interactions, and therapeutic applications. Recent advances highlight the therapeutic potential of targeting efferocytosis using modalities and biomaterial-based strategies. This review systematically examines the role of efferocytosis in osteoimmunology, discusses key challenges in its therapeutic translation, and explores emerging strategies to optimize efferocytosis-based interventions for inflammatory bone disorders.