Advancements of anticancer agents by targeting the Hippo signalling pathway: biological activity, selectivity, docking analysis, and structure-activity relationship.

IF 3.9 2区 化学 Q2 CHEMISTRY, APPLIED Molecular Diversity Pub Date : 2024-10-22 DOI:10.1007/s11030-024-11009-1
E Haripriya, K Hemalatha, Gurubasavaraja Swamy Purawarga Matada, Rohit Pal, Pronoy Kanti Das, M D Ashadul Sk, S Mounika, M P Viji, I Aayishamma, K R Jayashree
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Abstract

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.

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针对 Hippo 信号通路的抗癌药物研究进展:生物活性、选择性、对接分析和结构-活性关系。
Hippo 信号通路非常重要,它控制着细胞增殖和干细胞活性,是一种生长调节因子和肿瘤抑制因子。Hippo 信号通路的缺陷及其下游效应物 Yes-associated 蛋白(YAP)和具有 PDZ 结合基调的转录共激活因子(TAZ)的过度激活在癌症发展中起着作用,这意味着药物抑制 YAP 和 TAZ 的活性可能是一种有效的癌症治疗策略。相反,YAP 和 TAZ 也能在损伤后促进组织修复和再生,因此在某些情况下激活它们可能会有治疗效果。最近,人们发现了影响 YAP 和 TAZ 活性的复杂的细胞内外信号机制网络。YAP/TAZ-TEAD相互作用导致肿瘤发生,YAP/TAZ-TEAD的蛋白质结构包括三个界面和一个疏水袋。目前已有临床和临床前试验药物可用于抑制海马信号通路,但这些药物具有中度到严重的副作用,因此研究人员正在寻找新型、强效和选择性的海马信号通路抑制剂。在这篇综述中,我们详细讨论了河马信号通路,包括其结构、激活和在癌症中的作用。我们还提供了正在进行临床和临床前试验的各种抑制剂,以及小分子抑制剂的详细对接分析、结构-活性关系和生物活性。我们希望本研究能成为研究人员的有用资源。
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来源期刊
Molecular Diversity
Molecular Diversity 化学-化学综合
CiteScore
7.30
自引率
7.90%
发文量
219
审稿时长
2.7 months
期刊介绍: Molecular Diversity is a new publication forum for the rapid publication of refereed papers dedicated to describing the development, application and theory of molecular diversity and combinatorial chemistry in basic and applied research and drug discovery. The journal publishes both short and full papers, perspectives, news and reviews dealing with all aspects of the generation of molecular diversity, application of diversity for screening against alternative targets of all types (biological, biophysical, technological), analysis of results obtained and their application in various scientific disciplines/approaches including: combinatorial chemistry and parallel synthesis; small molecule libraries; microwave synthesis; flow synthesis; fluorous synthesis; diversity oriented synthesis (DOS); nanoreactors; click chemistry; multiplex technologies; fragment- and ligand-based design; structure/function/SAR; computational chemistry and molecular design; chemoinformatics; screening techniques and screening interfaces; analytical and purification methods; robotics, automation and miniaturization; targeted libraries; display libraries; peptides and peptoids; proteins; oligonucleotides; carbohydrates; natural diversity; new methods of library formulation and deconvolution; directed evolution, origin of life and recombination; search techniques, landscapes, random chemistry and more;
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