摘要
背景:蛋白激酶B(PKB/Akt)属于相关的丝氨酸/苏氨酸激酶超家族,有3种结构同源的哺乳动物亚型:Akt 1(pkbα)、Akt 2(pkbβ)和aKT 3(Pk 3)。bγ)。除了具有相似的结构拓扑外,其生理功能和组织分布的差异使Akt成为涉及细胞生长的多种信号途径中的主要节点。h,生存和增殖。各种免疫组织化学研究报道,Akt信号的本构性过度激活与几种类型的人类癌症有关,预后较差。S,以及化疗和放射治疗的抗药性。因此,抑制Akt活化是诱导多种肿瘤细胞凋亡和逃避化疗的一个很有前途的概念。抵抗。然而,作为合适的拮抗剂,Akt激酶的强效和选择性抑制剂的发展仍然黯淡,因此,只有少数化合物被选择用于临床研究。但没有一种药物能够在临床上推广应用,以避免肿瘤细胞的增殖和对化疗药物的耐药性。最近关于实现异构体选择的报道通过设计抗Akt结构域的抑制剂,再加上Akt 1结构域晶体结构的可用性,为基于结构的设计提供了可能。 方法:本文介绍了Akt及其底物调控细胞生长和存活的各种生物调控网络,以及与分子doc相结合的几种合成孔径雷达(SAR)和量子合成孔径雷达(QSAR)策略。为了进一步探讨配体-Akt亚型相互作用的选择性,对Akt亚型的选择性抑制剂进行了金的研究。 结果:基于结构的药物设计研究表明,结构多样的化合物与cat结构域的Glu121、Ala 123、Asn 171、Asp184、Glu228和Ala 230氨基酸残基相互作用。NDArg 23、Arg 25、Lys 30、Asn 54和Arg 86氨基酸残基在PH结构域中发挥着重要的抑制作用。 结论:Akt的亚型选择性抑制可能具有临床意义,应在今后的研究中加以考虑。此外,一种最新的异构体选择性化学物质A需要进一步验证已经报道的异构体选择性结合假说。
关键词: 蛋白激酶B,PH结构域,Akt抑制剂,选择性,细胞凋亡,合理的分子设计。
图形摘要
Current Cancer Drug Targets
Title:Pharmacoinformatic Approaches to Design Novel Inhibitors of Protein Kinase B Pathways in Cancer
Volume: 18 Issue: 9
关键词: 蛋白激酶B,PH结构域,Akt抑制剂,选择性,细胞凋亡,合理的分子设计。
摘要: Background: Protein kinase B (PKB/Akt) belongs to the AGC superfamily of related serine/ threonine kinases with three structurally homologous mammalian isoforms, Akt1 (PKBα), Akt2 (PKBβ), and Akt3 (PKBγ). Besides sharing a similar structural topology, the difference in their physiological functions and tissue distribution makes Akt a cardinal node in diverse signaling pathways involving cell growth, survival, and proliferation. Various immunohistochemical studies have reported that the constitutive hyperactivation of Akt signaling is responsible for several types of human cancer, poor prognosis, as well as chemotherapeutic and radiotherapeutic resistance. Thus, inhibition of Akt activation represents a promising concept to induce cell apoptosis in various cancers and evade chemotherapeutic resistance. However, development of potent and selective inhibitors of Akt kinases as suitable antagonists remained gloomy and thus, only handful of compounds were selected for the clinical investigation but none of them could reach the market for routine clinical usage to circumvent cell proliferation and resistance to chemotherapeutic agents in cancer. Recent reports on achieving isoform selectivity by designing inhibitors against PH domain of Akt, together with availability of crystal structures of the PH domain of Akt1, open the possibility of structurebased design.
Methods: In this article, various biological regulatory networks by which Akt and its substrates regulate cell growth and survival and several SAR and QSAR strategies in combination with molecular docking studies on selective inhibitors of Akt subtypes have been highlighted to further probe the selectivity of ligand-Akt subtypes interactions.
Results: Structure-based drug design studies revealed that the interactions of structurally diverse compounds with Glu121, Ala123, Asn171, Asp184, Glu228 and Ala230 amino acid residues in CAT domain and Arg23, Arg25, Lys30, Asn54 and Arg86 amino acid residues within PH domain play an important role in attaining significant inhibitory potency.
Conclusion: Isoform selective inhibition of Akt might have clinical significance and thus, should be taken into account in future investigations. Moreover, an up to date isoform selective chemical data is required to further validate already reported isoform selective binding hypothesis.
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Cite this article as:
Pharmacoinformatic Approaches to Design Novel Inhibitors of Protein Kinase B Pathways in Cancer, Current Cancer Drug Targets 2018; 18 (9) . https://dx.doi.org/10.2174/1568009617666170623104540
DOI https://dx.doi.org/10.2174/1568009617666170623104540 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
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