The major safety concerns that lead to the termination of clinical drug development programs and the withdrawal of approved drugs from the market are related to the cardiovascular system and the liver. The most frequent cardiovascular adverse event that prompts drug withdrawals is the potentially life-threatening cardiac arrhythmia known as Torsades de Pointes (TdP). Sunitinib, a multi-targeted receptor tyrosine kinase inhibitor, has shown promise in treating various tumors but raises concerns regarding its cardiovascular safety. This study aims to comprehensively evaluate the proarrhythmic risks associated with Sunitinib, employing an integrated platform that spans both in vitro and ex vivo analyses.
As one of the important abnormal cytoplasmic DNA monitoring mechanisms, cGAS-STING signaling pathway plays a unique and critical role in host defense against pathogens, tumor immunity, autoimmune diseases, and aging-related inflammation. Sustained activation of the cGAS- STING signaling pathway drives diseases such as autoimmune diseases, aging-associated inflammation, and neurodegenerative pathologies. Therefore, designing drugs that activate/inhibit cGAS or STING signaling may be helpful in anti-cancer, anti-pathogen, anti-inflammatory and other fields. On this basis, we established a series of in vitro screening platforms related to cGAS-STING signaling pathways to facilitate the rapid identification of cGAS/STING agonists/inhibitors.
Intrinsic immunity is an important line of defense against pathogenic microorganisms, which can effectively fight and remove external dangers. However, dysfunction of innate and adaptive immunity is considered to be a key step in the initiation and maintenance of autoimmune diseases. NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is a multimeric protein complex, which can detect exogenous pathogen irritants and endogenous danger signals, which promote interleukin (IL)-1β and IL-18 secretion and pyroptosis mediated by caspase-1. Numerous studies have shown their significance in autoimmune diseases, such as rheumatoid arthritis (RA) and inflammatory bowel disease (IBD), which strongly indicate that NLRP3 inflammasome complex may serve as a promising and novel therapeutic target for clinical treatment in inflammatory-related diseases.
The Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathways are evolutionarily conserved transmembrane signaling mechanisms that ensure the ability of normal cellular communication with the external environment. Various cytokines, interferons, growth factors, and other specific molecules can activate JAK-STAT signaling to drive a range of physiological and pathological processes, including proliferation, metabolism, immune response, inflammation, and malignancy. However, the JAK-STAT signaling pathway and related gene mutations are closely associated with aberrant immune activation and cancer progression. Through extensive research into the structure and function of the JAK-STAT pathway, a variety of clinical drugs have emerged and been approved for the treatment of disease, primarily targeting cytokines and their receptors, JAK inhibitors and STAT inhibitors.
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