Trends in pharmacological sciences最新文献

In most drug discovery efforts targeting regulator of G-protein signaling (RGS) proteins, inhibiting their activity is the end-goal. A recent article by Aryal et al. presents a novel strategy to stabilize RGS2 by blocking its degradation via the ubiquitin-proteasomal system rather than inhibiting its function, a shift from developing small-molecule inhibitors targeting RGS proteins to modulate G-protein-coupled receptor (GPCR) signaling.

Historically, the clinical application of cell-free RNA (cfRNA) liquid biopsies has been limited by background noise. In a recent study, Nesselbush et al. developed a method for denoising cfRNA analysis, resulting in RARE-seq, a versatile liquid biopsy platform that enables transcriptomic profiling, and cancer detection and monitoring, unlocking the potential of this exciting analyte.

Glycans are complex sugar modifications found on cell surfaces that play crucial roles in biological processes. Glycosylation patterns are aberrantly altered in the tumor microenvironment (TME), which helps cancer cells escape immune surveillance by creating a tumor-specific 'glyco-code' that weakens immune responses and reduces immunotherapy effectiveness. Recent studies have illustrated the potential to improve antitumor immune responses by manipulating glycosylation in the TME. We review the effects of aberrant glycosylation on the regulation of tumor immunity and the corresponding strategies for manipulating glycosylation to enhance antitumor immunity. These strategies include inhibiting glycan-receptor interactions, engineering cell-surface glycans, and remodeling the extracellular matrix. This Review highlights the importance of glycosylation in designing effective and personalized cancer treatments.

Diabetic retinopathy (DR) and nephropathy (DN) are leading microvascular complications of diabetes, yet current therapies remain inadequate. Fenofibrate, a peroxisome proliferator-activated receptor (PPAR)-α agonist approved for dyslipidemia, has gained attention for its protective effects on the retina and kidney that extend beyond lipid modulation. Emerging preclinical and clinical evidence highlights the pleiotropic actions of fenofibrate (anti-inflammatory, antioxidative, neuroprotective, and antifibrotic), mediated through both PPAR-α-dependent and -independent pathways. These properties support its potential benefits in DR and DN, even in normolipidemic individuals. In this review, we integrate mechanistic insights with clinical outcomes, critically evaluate landmark trials, and explore emerging molecular targets of fenofibrate. We highlight the multifunctional actions of fenofibrate and propose strategies to advance its clinical utility in diabetic microvascular complications.

Despite the development of new classes of therapeutics in oncology, patients with tumors harboring mutations in the tumor suppressor gene STK11/LKB1 continue to exhibit poor clinical response and therapeutic resistance. Recent advances in the understanding of LKB1-mutant tumor biology have illuminated how metabolism and the tumor microenvironment (TME) function as effectors of the aggressive nature of this tumor type. New findings have revealed how metabolic reprogramming, a hallmark of LKB1-mutant tumor biology, can be exploited as a potential targetable liability in these tumors. Characterization of the distinctly immunosuppressive LKB1-mutant TME has motivated multiple discoveries of new approaches for rewiring the microenvironment to overcome immunotherapy resistance. Indeed, overcoming therapeutic resistance in LKB1-deficient tumors continues to be a major research focus, and some preclinical studies have advanced to clinical trials. In this review, we critically analyze these findings and discuss therapies in development that aim to leverage this new understanding for clinical benefit.

Long noncoding RNAs (lncRNAs) play a pivotal role in regulating cellular processes, and their dysregulation has been linked to the progression of disease. Understanding the structural characteristics, protein interactions, and expression dynamics of lncRNAs is essential for deciphering their functional mechanisms. Recent advancements in structural probing techniques have unveiled critical structural motifs and RNA-protein interfaces that contribute to lncRNA dysfunction. Furthermore, developing small molecules, antisense oligonucleotides, and peptidomimetic-based therapeutic agents that target these motifs and interfaces presents promising strategies for treating lncRNA-mediated diseases. This review provides fresh insights into how lncRNAs contribute to disease pathogenesis, focusing on well-characterized lncRNAs, including MALAT1, HOTAIR, GAS5, NEAT1, and XIST as case studies, and explores potential therapeutic agents targeting these lncRNAs to support future drug development efforts.

Alzheimer's disease (AD) and cancer are immune-mediated disorders characterized by chronic neuroinflammation and immune evasion, respectively. Recent studies implicate two key immune regulators in both diseases: LAG-3, an adaptive immune checkpoint receptor, and TREM2, an innate receptor expressed on microglia and tumor-associated macrophages (TAMs). LAG-3 inhibitors have demonstrated clinical efficacy in cancer and are being explored in AD research. TREM2 activation supports microglial function in AD, while its inhibition may counteract immunosuppressive macrophages in cancer. In this review we compare the roles, mechanisms, and therapeutic strategies targeting LAG-3 and TREM2 in both diseases. We highlight their distinct immune compartmentalization and the importance of context-specific modulation. Strategies include LAG-3 blockade in cancer and AD, and TREM2 agonism or antagonism depending on disease context. We discuss a framework integrating immune compartment, disease state, and therapeutic modality to guide cross-domain immunotherapy development in cancer and AD.

Synthetic glucocorticoids (GCs) are effective anti-inflammatory drugs but cause serious adverse effects (AEs). Initially, anti-inflammatory efficacy and AEs were ascribed to GC receptor (GR)-mediated gene transrepression and transactivation, respectively. Although current evidence indicates greater mechanistic complexity of GC action, this proposed distinction in GR-mediated effects has led to the design of novel steroidal and nonsteroidal GR modulators (GRMs) using emerging technologies and new laboratory assays to reduce the AEs associated with synthetic GCs. These GRMs alter the balance between GR transrepression and transactivation. A novel GRM, the dissociated steroid vamorolone, received marketing approval in 2024, confirming that altering the transrepression-transactivation profile is a valid strategy. Here, we review GR-mediated gene regulation and the transrepression-transactivation profile of GCs in relation to their anti-inflammatory efficacy and AEs. We highlight technological advances driving the design/development of novel GRMs, such as selective GR agonists and modulators (SEGRAMs), and provide insights into their mechanism of action.

Identification of therapeutic vulnerabilities in cancer remains a high priority for cancer research. A recent CRISPR/Cas9 screen identified that VDAC2 deletion in tumors enhanced their sensitivity to interferon-γ (IFNγ) through the release of mitochondrial DNA (mtDNA) and activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. These data suggest that VDAC2 inhibition could enhance antitumor therapies.