Trends in pharmacological sciences最新文献

Before molecular pathways in cancer were known to a depth that could predict targets, drug development relied on phenotypic screening, where the effectiveness of candidate chemicals is judged from functional readouts without considering the mechanisms of action. The unraveling of tumor-specific pathways has brought targets for molecularly driven drug discovery, but precedents in the field have shown that awareness of pathways does not necessarily predict therapeutic efficacy, and many cancers still lack druggable targets. Phenotypic screening therefore retains a niche in drug development where a targeted approach is not informative. We analyze the unique advantages of phenotypic screens, and how technological advances have improved their discovery power. Notable advances include the use of larger biological panels and refined protocols that address the disease-relevance and increase data content with imaging and omic approaches.

Selenoprotein glutathione peroxidase 4 (GPX4) serves as a crucial suppressor of oxidative stress-induced ferroptosis, making it an attractive target for disease therapy. Here, we discuss recent strategies and challenges associated with targeting GPX4 through covalent inhibitors, proteolysis targeting chimera (PROTAC) degraders, and cell-type-specific degraders in the context of cancer.

PANoptosis is a unique innate immune inflammatory lytic cell death pathway initiated by an innate immune sensor and driven by caspases and RIPKs. As a distinct pathway, the execution of PANoptosis cannot be hindered by targeting other cell death pathways, such as pyroptosis, apoptosis, or necroptosis. Instead, targeting key PANoptosome components can serve as a strategy to prevent this form of cell death. Given the physiological relevance in several diseases, PANoptosis is a pivotal therapeutic target. Notably, previous research has primarily focused on the role of PANoptosis in cancer and infectious and inflammatory diseases. By contrast, its role in cardiovascular diseases has not been comprehensively discussed. Here, we review the available evidence on PANoptosis in cardiovascular diseases, including cardiomyopathy, atherosclerosis, myocardial infarction, myocarditis, and aortic aneurysm and dissection, and explore a variety of agents that target PANoptosis, with the overarching goal of providing a novel complementary approach to combatting cardiovascular diseases.

Achieving the efficacy and specificity of G-protein-coupled receptor (GPCR) targeting-drugs in the skin remains challenging. Understanding the molecular mechanism underlying GPCR dysfunction is crucial for developing targeted therapies. Recent advances in genetic, signal transduction, and structural studies have significantly improved our understanding of cutaneous GPCR functions in both normal and pathological states. In this review, we summarize recent discoveries of pathogenic GPCRs in dermal injuries, chronic inflammatory dermatoses, cutaneous malignancies, as well as the development of potent potential drugs. We also discuss targeting of cutaneous GPCR complexes via the transient receptor potential (TRP) channel and structure elucidation, which provide new opportunities for therapeutic targeting of GPCRs involved in skin disorders. These insights are expected to lead to more effective and specific treatments for various skin conditions.

Bruton’s tyrosine kinase (BTK) inhibitors have revolutionized the treatment landscape for B cell lymphomas such as chronic lymphocytic leukemia (CLL). The first-in-class BTK inhibitor ibrutinib has recently been succeeded by covalent BTK inhibitors that are safer but still face challenges of resistance mutations. The noncovalent BTK inhibitor pirtobrutinib was recently approved for relapsed and refractory CLL, and whether noncovalent BTK inhibitors will supplant covalent BTK inhibitors as upfront treatment options either alone or in combination will be determined. Meanwhile, newer BTK inhibitors and BTK degraders are vying for their place in the potential future landscape of B cell cancers as well as autoimmune diseases. This review will cover the latest progress in BTK inhibitor development and where the field is moving in light of these recent discoveries.

Growing evidence suggests that metabolic dysfunction-associated steatotic liver disease (MASLD) is significantly higher in men versus women. Increased prevalence is observed in postmenopausal women, suggesting that age and sex (hormones) influence MASLD development and progression. Molecular data further reveal that sex regulates the innate immune responses with an essential role in MASLD progression. To date, there has been limited focus on the role of innate immune sexual dimorphism in MASLD, and differences between men and women are not considered in the current drug discovery landscape. In this review, we summarize the sex disparities and innate immune sexual dimorphism in MASLD pathogenesis. We further highlight the importance of harnessing sexual dimorphism in identifying therapeutic targets, developing pharmacological therapies, and designing (pre-) clinical studies for the personalized treatment for MASLD.

Extracellular histones instigate an inflammatory triad - centered on cytotoxicity, immune cell stimulation, and coagulation - ultimately shaping the dynamics and outcome of various inflammatory pathologies. Given the virtual absence of beneficial functions of histones in the extracellular space, in recent years a number of interference strategies have emerged. In this review we summarize pathogenic functions of extracellular histones and highlight current developments of therapeutic interference. Finally, we elaborate on the current status of preclinical attempts to interfere with extracellular histones in the context of a focus on sepsis and cardiovascular diseases, both of which are leading causes of mortality worldwide.

Peptide arrays are a valuable instrument in the characterization of protein-protein interactions (PPIs) and immunogenic regions. New methods were developed to exploit the high-throughput potential of peptide arrays to obtain more in-depth information, replacing traditional resource-intensive experiments. Here, we discuss the recent advances in peptide-array-based technologies and the remaining challenges.