Fujita Minami, Demizu Yosuke
Division of Organic Chemistry, National Institute of Health Sciences 3-25-26, Tonomachi Kawasaki Kanagawa 210-9501 Japan
Graduate School of Medical Life Science, Yokohama City University 1-7-29 Yokohama Kanagawa 230-0045 Japan.
RSC Med Chem. 2024 Dec 2. doi: 10.1039/d4md00749b.
The Wnt/β-catenin signaling pathway plays a critical role in various biological processes, including cell proliferation, differentiation, and tissue homeostasis. Aberrant activation of this pathway is strongly associated with the development of various cancers, including colorectal, pancreatic, and gastric cancers, making it a promising therapeutic target. In recent years, inhibitors targeting different components of the Wnt/β-catenin pathway, including small molecules, peptides, and nucleic acid-based therapies, have been developed to suppress cancer cell growth. These inhibitors work by disrupting key interactions within the pathway, thereby preventing tumor progression. Antibody-based therapies have also emerged as potential strategies to block ligand-receptor interactions within this pathway. Despite these advancements, challenges such as the complexity of the pathway and toxicity concerns remain. Innovative approaches, including allosteric inhibitors, proteolysis-targeting chimeras (PROTACs), and peptide-based inhibitors, offer new opportunities to address these challenges. This review provides an overview of the latest progress in the development of Wnt/β-catenin pathway inhibitors and explores future directions in cancer therapy.
Wnt/β-连环蛋白信号通路在多种生物学过程中发挥着关键作用，包括细胞增殖、分化和组织稳态。该通路的异常激活与包括结直肠癌、胰腺癌和胃癌在内的多种癌症的发生密切相关，使其成为一个有前景的治疗靶点。近年来，已开发出针对Wnt/β-连环蛋白通路不同组分的抑制剂，包括小分子、肽和基于核酸的疗法，以抑制癌细胞生长。这些抑制剂通过破坏通路内的关键相互作用发挥作用，从而阻止肿瘤进展。基于抗体的疗法也已成为阻断该通路内配体-受体相互作用的潜在策略。尽管取得了这些进展，但诸如通路复杂性和毒性问题等挑战依然存在。创新方法，包括变构抑制剂、蛋白酶靶向嵌合体（PROTAC）和基于肽的抑制剂，为应对这些挑战提供了新机遇。本综述概述了Wnt/β-连环蛋白通路抑制剂开发的最新进展，并探讨了癌症治疗的未来方向。
