Haripriya E, Hemalatha K, Matada Gurubasavaraja Swamy Purawarga, Pal Rohit, Das Pronoy Kanti, Ashadul Sk M D, Mounika S, Viji M P, Aayishamma I, Jayashree K R
Integrated Drug Discovery Centre, Department of Pharmaceutical Chemistry, Acharya & BM Reddy College of Pharmacy, Bengaluru, 560107, Karnataka, India.
Mol Divers. 2025 Jun;29(3):2829-2862. doi: 10.1007/s11030-024-11009-1. Epub 2024 Oct 22.
The Hippo signalling pathway is prominent and governs cell proliferation and stem cell activity, acting as a growth regulator and tumour suppressor. Defects in Hippo signalling and hyperactivation of its downstream effector's Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) play roles in cancer development, implying that pharmacological inhibition of YAP and TAZ activity could be an effective cancer treatment strategy. Conversely, YAP and TAZ can also have beneficial effects in promoting tissue repair and regeneration following damage, therefore their activation may be therapeutically effective in certain instances. Recently, a complex network of intracellular and extracellular signalling mechanisms that affect YAP and TAZ activity has been uncovered. The YAP/TAZ-TEAD interaction leads to tumour development and the protein structure of YAP/TAZ-TEAD includes three interfaces and one hydrophobic pocket. There are clinical and preclinical trial drugs available to inhibit the hippo signalling pathway, but these drugs have moderate to severe side effects, so researchers are in search of novel, potent, and selective hippo signalling pathway inhibitors. In this review, we have discussed the hippo pathway in detail, including its structure, activation, and role in cancer. We have also provided the various inhibitors under clinical and preclinical trials, and advancement of small molecules their detailed docking analysis, structure-activity relationship, and biological activity. We anticipate that the current study will be a helpful resource for researchers.
河马信号通路十分重要，它调控细胞增殖和干细胞活性，起到生长调节因子和肿瘤抑制因子的作用。河马信号通路缺陷及其下游效应蛋白Yes相关蛋白（YAP）和含PDZ结合基序的转录共激活因子（TAZ）的过度激活在癌症发展中发挥作用，这意味着对YAP和TAZ活性进行药理学抑制可能是一种有效的癌症治疗策略。相反，YAP和TAZ在促进损伤后的组织修复和再生方面也可能具有有益作用，因此在某些情况下激活它们可能具有治疗效果。最近，已经发现了一个影响YAP和TAZ活性的细胞内和细胞外信号传导机制的复杂网络。YAP/TAZ-TEAD相互作用会导致肿瘤发展，YAP/TAZ-TEAD的蛋白质结构包括三个界面和一个疏水口袋。有临床和临床前试验药物可用于抑制河马信号通路，但这些药物有中度到重度的副作用，因此研究人员正在寻找新型、强效和选择性的河马信号通路抑制剂。在这篇综述中，我们详细讨论了河马信号通路，包括其结构、激活以及在癌症中的作用。我们还提供了正在进行临床和临床前试验的各种抑制剂，以及小分子的进展、它们的详细对接分析、构效关系和生物活性。我们预计当前的研究将为研究人员提供有用的资源。
