Trends in pharmacological sciences最新文献

FLT3 mutations drive acute myeloid leukemia (AML) progression through aberrant signaling, making FLT3 inhibition a key therapeutic strategy. Current inhibitors show efficacy, yet resistance and toxicity remain challenges. Emerging approaches, including selective inhibitors, proteolysis-targeting chimeras, and protein degraders, offer enhanced potency, sustained suppression, and combinatorial potential, representing a precision-based advancement in AML treatment.

Proteins involved in signaling networks, such as Ras, mammalian target of rapamycin (mTOR), and epidermal growth factor receptor (EGFR), exist as dynamic conformational ensembles in biomolecular condensates. These ensembles play a crucial role in allosteric drug discovery and action. Traditional approaches in drug discovery often trace back to the induced fit model, which viewed proteins as rigid entities with active and inactive states. However, this model's limitations hindered successful drug development. Advanced molecular dynamics simulations of oncogenic mutants and experiments reveal heterogeneous dynamic ensembles, which can uncover targetable spots like cryptic pockets and cooperative exosites that only exist transiently. In this review, we clarify traditional dogmas and show how recent knowledge improves allosteric drug design by leveraging conformational ensembles, with examples. We further discuss how ensemble-based approaches can advance promising therapeutics, unlocking their potential for more effective future strategies, including in biomolecular condensates.

The palmitoylation/depalmitoylation cycle regulates protein localization, function, and stability, playing essential roles in signal transduction, membrane trafficking, and neuronal activity. Understanding the enzymes involved may reveal novel therapeutic targets. Palmitoyl-protein thioesterase-1 (PPT1) is a key depalmitoylase that removes palmitate from target proteins. Deficiency in PPT1 causes Batten disease (CLN1), a fatal neurodegenerative disorder, while overexpression has been linked to various cancers. Emerging evidence also implicates PPT1 in other neurodegenerative, autoimmune, and reproductive diseases. Recognizing its broad biological significance, PPT1 is an enzyme with growing therapeutic interest; however, translational hurdles still remain. This review provides an overview of PPT1 structure, enzymatic activity, substrates, and roles across systems, alongside a landscape of PPT1-targeted drugs in preclinical and clinical development that will inform future research.

G protein-coupled receptors orchestrate numerous physiological processes and represent the largest class of drug targets, yet their intracellular regulators, the β-arrestins, remain largely underexplored. Despite their crucial roles in receptor desensitization, trafficking, and signaling, few modulators have been identified, with limited isoform selectivity. Therapeutic efforts have mainly focused on receptor-level biased ligands to indirectly influence arrestin pathways. However, advances in small-molecule discovery and peptide design are now expanding the feasibility of directly modulating β-arrestins using structurally tailored ligands, primarily as research tools and potential therapeutic leads. Along with the recent identification of disease-associated mutations and first-generation modulators, these developments create new opportunities for selective and mutation-specific targeting. In this review, we summarize β-arrestin biology and signaling, highlight recent discoveries of disease-associated mutations and β-arrestin modulators, and discuss emerging strategies for precision drug development of arrestin-targeting compounds, with a focus on peptides.

Metabolism modulation has emerged as a promising frontier in precision oncology. Nonetheless, the primary gap is the inability to precisely target the unique metabolic vulnerabilities of different cell types in vivo, which has limited clinical translation. Recent strategies that integrate tumor metabolism with advanced delivery systems are now enabling targeted metabolic intervention. In light of these developments, we evaluate current progress and highlight a path forward for metabolism-modulating drug delivery systems (MDDSs) in precision oncology. We also dissect key translational barriers-including metabolic heterogeneity, biological barriers, and off target effects-and discuss challenges in preclinical validation and clinical translation. Moreover, we propose emerging solutions-including metabolic circuit mapping, artificial intelligence-driven carrier design, and integrated MDDS platforms-to further advance the development of precision metabolism-based therapeutics.

Targeted alpha therapy (TAT) delivers localized, high linear energy transfer (LET) radiation that induces irreparable DNA damage, particularly double-strand breaks, leading to selective tumor cell death. Alpha emitters are gaining interest due to their potent efficacy and favorable safety profiles compared with conventional treatments. Advances in chelator design have enabled the formation of highly stable chelating complexes or covalent binding to targeting molecules. Actinium-225, astatine-211, and lead-212 are the most promising and clinically advanced alpha-emitting radionuclides. However, scaling up production and ensuring a sustainable global supply remain major challenges. This review highlights recent progress in radionuclide production, radiochemistry, chelator development, and tumor-targeting strategies and examines the current landscape of clinical trials involving these three alpha emitters.

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.

The bioenergetic crisis in cancer cachexia arises from early mitochondrial dysfunction that precipitates muscle wasting. In a recent study, Angelino et al. found that tumor-derived signals suppress the cAMP-protein kinase A (PKA)-CREB1 axis, destabilizing mitochondrial homeostasis. Restoring cAMP signaling through phosphodiesterase 4 (PDE4) inhibition rescued mitochondrial function, highlighting a promising strategy to mitigate tumor-induced cachexia.