STAT3 inhibitors(Zhejiang Chinese Medical University)

Colorectal cancer (CRC) has become a significant threat in recent decades, and its incidence is predicted to continue rising. Despite notable advancements in therapeutic strategies, managing CRC poses complex challenges, primarily due to the lack of clinically feasible therapeutic targets. Among the myriad molecules implicated in CRC, the signal transducer and activator of transcription 3 (STAT3) stands out as a promising target tightly regulated by various genes. This intracellular transcription factor, spanning 750-795 amino acids and weighing approximately 92 kDa, is crucial in key cellular activities such as growth, migration, invasion, inflammation, and angiogenesis. Aberrant activation of STAT3 signaling has been linked to various cancers, including CRC. Therefore, targeting this signaling pathway holds significance for potential CRC treatment strategies. STAT3, as a central intracellular transcription factor, is implicated in colorectal cancer development by activating aberrant signaling pathways. Numerous studies have demonstrated that the abnormal hyperactivation of STAT3 in CRC tissues enhances cell proliferation, suppresses apoptosis, promotes angiogenesis, and facilitates tumor invasion and metastasis. As a focal point in colorectal cancer research, STAT3 emerges as a promising candidate for detecting and treating CRC. This review aims to present recent data on STAT3, emphasizing the activation and functions of STAT3 inhibitors in CRC. Indeed, STAT3 inhibitors have been identified to have therapeutic potential in CRC, especially inhibitors targeting the DNA-binding domain (DBD). Indeed, STAT3 inhibitors have been identified to have a therapeutic potential in CRC, especially the inhibitors targeting the DNA binding domain (DBD). For example, imatinib acts by targeting cell surface receptors, and these inhibitors have shown potential for the control and treatment of tumor growth, angiogenesis, and metastasis. Imatinib, for example acts by targeting cell surface receptors, and these inhibitors have shown the future direction toward the control and treatment of tumor growth, angiogenesis, and metastasis.

Breast cancer stem cells (BCSCs) are pivotal in tumor initiation, progression, and therapeutic resistance, underscoring the need for targeted interventions. Signal transducer and activator of transcription 3 (STAT3) has been implicated in maintaining cancer stemness, representing a compelling therapeutic target. Here, we describe the structure-guided optimization of Juglone, yielding novel STAT3 inhibitors with improved potency. The representative compound 35 (YZ-35) demonstrated potent STAT3 phosphorylation and exhibited nanomolar affinity in binding assays (IC₅₀ = 190 nM). YZ-35 exhibited remarkable antiproliferative activity across multiple breast cancer cell lines and selectively suppressed BCSC self-renewal, outperforming TTI-101 and matching BBI-608 in potency. In vivo, YZ-35 achieved approximately 90% tumor growth inhibition (10 mg/kg) in xenograft models, with reduced toxicity versus paclitaxel. Mechanistic studies confirmed STAT3 pathway disruption and BCSC depletion. These results highlight YZ-35 as a natural product-derived STAT3 inhibitor with dual antitumor and anti-CSC activity, offering a translational strategy for refractory BRCA.