Trends in pharmacological sciences最新文献

Siglecs are a family of sialic acid-binding immunoglobulin-like lectins that regulate immune signaling and maintain homeostasis through glycan recognition. Despite their central role in immune modulation, their therapeutic potential remains underexplored. Advances in antibody engineering, glycan biology, and molecular design have greatly expanded our understanding of Siglec-ligand interactions, revealing their promise in regulating immunosuppression in cancer and autoimmunity. The current clinical landscape shows trials targeting mainly Siglec-2 and -3, with a predominant focus on hematological cancers. This review evaluates preclinical and recent clinical progress in Siglec-targeted immunotherapies, emphasizing mechanisms, safety, and efficacy, and proposes a translational framework to accelerate therapy development and broader immunotherapy advancements.

Men experience higher cancer incidence and mortality than women, and accumulating evidence implicates androgen receptor (AR) signaling as a key biological driver of these sex-based disparities. AR signaling can suppress adaptive anticancer immunity. Preclinical studies across multiple cancer types show that AR inhibition enhances T cell function and sensitizes tumors to immune checkpoint inhibition. However, recent Phase 3 trials combining AR suppression with immune checkpoint blockade in prostate cancer (PCa) failed to demonstrate clinical benefit. We discuss these developments and summarize recent studies defining the role of AR signaling in anticancer immunity. We propose strategies to translate emerging insights into rational trial designs that optimize the integration of AR suppression with immunotherapy.

Membrane proteins are essential for cellular physiology and the target of half of all FDA-approved drugs. However, their hydrophobicity and low abundance make large-scale expression and purification difficult, posing a challenge for drug discovery. Despite these problems, mass spectrometry (MS) has enabled workflows for higher-throughput ligand screening, simplified identification of membrane protein targets and ligandable sites, and direct analysis of drug binding in native environments. In this review, we highlight emerging MS-based strategies, adapted workflows, and novel technological advances in different MS-based fields, including affinity selection, probe-based and probe-free chemoproteomics, and native MS that collectively expand our ability to interrogate membrane proteins for drug discovery, target deconvolution, and mechanistic characterization.

Biased signaling by G protein-coupled receptors (GPCRs) occurs when ligands selectively activate G proteins or β-arrestins, offering therapeutic potential with fewer side effects. In class A GPCRs, which include the targets of approximately one-third of all marketed drugs, the structural basis of this selectivity remains unclear. Recent cryo-electron microscopy studies, supported by real-time functional assays such as bioluminescence resonance energy transfer and NanoLuc Binary Technology, reveal how distinct ligand binding modes reshape receptor conformations to favor specific transducer engagement. Integrating structural and functional insights enables mapping of isoform- and tissue-specific signaling. Here, we review key mechanisms of bias, including microswitch transitions, intracellular interface remodeling, and allosteric modulation, and provide a mechanistic basis for pathway-selective GPCR-targeting therapeutics with improved efficacy and reduced off-target effects.

Proposed budget cuts to the National Institutes of Health (NIH) by the current administration pose significant risk to academic and small biopharma drug discovery in the USA. Yet even in this challenging climate, there are viable strategies to ensure continued scientific progress. We highlight several approaches, including harnessing the power of artificial intelligence (AI), diversifying funding sources, accelerating commercialization and licensing, fostering new global collaborations, and strengthening public engagement in science.

Fluorescent RNAs (FRs), RNA mimics of fluorescent proteins (FPs), have emerged as a promising approach for tagging RNAs and investigating their complex spatiotemporal dynamics and biological functions. Moreover, FR-derived biosensors (FRBs) also provide useful tools for point-of-care testing of a wide range of targets, from small molecules, nucleic acids, and proteins to various pathogens. However, it is still unclear whether and how FRs and FRBs can be used to accelerate drug discovery. In this review article, we briefly summarize the recent advances in FRs and FRBs and focus on recent works showing how FRs and FRBs can be used during different stages of RNA and small-molecule drug discovery. Furthermore, we discuss limitations of current technologies and potential pathways for moving forward.

There is growing interest in developing psychedelic-inspired drugs for treating psychiatric disorders. However, identifying next-generation psychedelic analogs with ideal receptor selectivity and true therapeutic efficacy remains a major challenge. Recent progress has been driven by advances in determining agonist-induced biased signal transduction, high-content behavioral phenotyping via automated video analysis, drug-evoked structural neural remodeling, and activity-dependent gene expression. In this review, we outline a framework for evaluating psychedelics and non-hallucinogenic serotonin 2A (5-HT_2A) receptor agonists. We critically examine current methods for assessing (A) agonism, (B) behavior, and (C) cellular plasticity. We highlight emerging techniques that may improve translation to humans. We contend that an effective discovery pipeline must align with specific experimental goals and incorporate multiple approaches to be successful for psychedelic drug development.