PI3K/mTOR信号通路及双重抑制剂NVP-BEZ235的开发

磷脂酰肌醇3-激酶/蛋白激酶B/雷帕霉素靶蛋白(PI3K/Akt/mTOR)信号通路与肿瘤的发生发展密切相关.PI3K/mTOR双重抑制剂已成为抗肿瘤药物研发的热点之一.近年,NVP-BEZ235因其能有效并特异性地双重抑制PI3K/mTOR信号通路的异常活化而受到关注.本文综述PI3K/Akt/mTOR信号通路及NVP-BEZ235的开发.     

喹唑啉酮类选择性PI3Kδ抑制剂的研究进展

磷脂酰肌醇3-激酶δ(PI3Kδ)主要分布在造血细胞和免疫细胞中,对于B细胞的活化、增殖非常重要。PI3Kδ抑制剂可用于免疫相关的疾病与血液肿瘤的治疗。PI3Kδ抑制剂的化学结构多种多样,其中喹唑啉酮类选择性PI3Kδ抑制剂能诱导PI3Kδ构象的改变,是螺旋桨型PI3Kδ抑制剂的代表。本文基于喹唑啉酮类选择性PI3Kδ抑制剂与铰链区结合的结构不同(分为嘌呤类、吡唑并嘧啶类、嘧啶类),对近年来喹唑啉酮类选择性PI3Kδ抑制剂的最新研究进展进行综述。     

PI3K/Akt/mTOR信号通路与肿瘤

在近年来的肿瘤治疗中,靶向生物治疗逐渐成为研究的热点。该文就磷脂酰肌醇3-激酶/蛋白激酶B/哺乳动物雷帕霉素靶蛋白[phosphatidylinositol-3-kinase(PI3K)/protein kinase B(Akt)/the mammalian target of Rapamycin(mTOR),PI3K/Akt/mTOR]信号通路予以综述,重点包括PI3K/Akt/mTOR信号转导在肿瘤机制中作用以及肿瘤治疗过程中耐药性方面的关系等。     

磷脂酰肌醇-3磷酸激酶/AKT/雷帕霉素靶蛋白信号通路参与中枢神经损伤保护与修复的研究进展

中枢神经细胞对各种损伤刺激耐受差,损伤后神经修复困难.因此促进神经保护增强神经再生能力已成为神经治疗关键.磷脂酰肌醇-3磷酸激酶/AKT/雷帕霉素靶蛋白(PI3K/AKT/mTOR)信号通路是调节细胞周期的重要通路,在细胞增殖、生长、分化过程中起中心调控作用,在神经损伤过程中通过激活PI3K/AKT/mTOR信号通路可减少神经细胞死亡,促进神经修复.该文对PI3K/AKT/mTOR信号通路在中枢神经损伤保护作用、修复机制及可能风险作一综述,探讨将PI3K/AKT/mTOR信号通路作为靶点治疗中枢神经疾病.     

高糖激活PI3K/AKT/mTORC1通路诱导人肾小管上皮细胞骨桥蛋白的表达

目的探讨高糖刺激上调人肾小管上皮细胞株(HK-2)骨桥蛋白(OPN)表达的分子机制。方法利用高糖(25mmol·L-1)刺激HK-2细胞,并应用特异性抑制剂、siRNA抑制PI3K和(或)mTOR活性,应用Real-time PCR检测OPN mRNA表达;Western blot检测OPN、p-AKT、p-S6、Raptor和Rictor蛋白表达。结果高糖刺激呈时间依赖性上调HK-2细胞OPN表达,其中,OPN mRNA在刺激48h后达高峰;OPN蛋白表达在72h达到最高。此外,高糖刺激激活PI3K/AKT/mTORC1信号通路。利用PI3K特异性抑制剂LY294002、mTORC1特异性抑制剂rapamycin抑制PI3K/AKT/mTOR通路后,HK-2细胞的OPN表达明显降低。进一步,siRNA敲低Raptor降低HK-2细胞中OPN蛋白的表达,而敲低Rictor对OPN蛋白表达无影响。结论高糖通过激活PI3K/AKT/mTORC1通路上调HK-2细胞OPN的表达。     

选择性PI3K抑制剂的研究进展

磷脂酰肌醇3-激酶（PI3K）是细胞内重要的信号转导分子,在细胞存活、增殖和分化过程中起重要调节作用。PI3K是PI3K/AKT/mT0R信号转导通路中的关键节点蛋白,调控着重要的生命活动。现已证实磷脂酰肌醇3-激酶（PI3Ks）是潜力巨大的药物治疗靶点,特别是PI3Kα现己成为抗肿瘤治疗的重要靶点之一。目前己有多种针对PI3Ks的抑制剂进入临床研究。然而现有抑制剂的化学类型不多且选择性不高、临床应用受局限。因此积极研究和开发结构新颖的PI3K选择性抑制剂对于疾病的靶向治疗具有重要意义。本文将对选择性PI3K抑制剂在抗肿瘤方面的研究进展作一综述。     

PI3Kα/β选择性抑制剂的设计策略探析

目的 研究PI3K α/β选择性抑制剂设计策略.方法 运用分子对接、分子动力学模拟、结合自由能计算和量子化学计算等方法分析PI3Kα/β选择性抑制剂与PI3K α/β的结合方式.结果 与结论亚型选择性抑制剂与PI3K α/β结构之间的空间匹配和能量匹配存在差异,PI3Kα中Val851和PI3Kβ中Val848等残基对...     

PI3Kδ抑制剂在B细胞淋巴瘤中的应用情况

PI3K/AKT/mTOR信号通路在细胞的增殖、存活、分化、运动和胞内运输等生物功能中发挥了至关重要的作用。PI3Kδ作为PI3K的一个亚型,在B淋巴细胞中高表达并参与了B细胞淋巴瘤的恶性进展。因此,开发以PI3Kδ为靶点的抑制剂已成为抗B细胞淋巴瘤研究领域的热点。目前,已有多种PI3Kδ抑制剂被FDA批准用于B细胞淋巴瘤的治疗,其各具特点,但在临床上也存在着不同程度的不良反应。由于B细胞淋巴瘤发病机制的复杂性及多样性,单靶点的PI3Kδ抑制剂疗效往往有限,且易产生耐药性,常需联合化疗或其他靶向药物以提升疗效。PI3Kδ抑制剂的未来发展趋势是开发高效低毒的新型抑制剂,或者探索与化疗、放疗及靶向药物等联合运用以达到更好的抗肿瘤效果同时减少不良反应的治疗方案。本文将针对已上市和尚处于临床研究阶段的PI3Kδ抑制剂进行综述,重点围绕其作用特点、不良反应及联合用药方案。     

Drug resistance in non-hodgkin lymphomas

PI3K/AKT/mTOR信号通路在细胞的增殖、存活、分化、运动和胞内运输等生物功能中发挥了至关重要的作用。PI3Kδ作为PI3K的一个亚型,在B淋巴细胞中高表达并参与了B细胞淋巴瘤的恶性进展。因此,开发以PI3Kδ为靶点的抑制剂已成为抗B细胞淋巴瘤研究领域的热点。目前,已有多种PI3Kδ抑制剂被FDA批准用于B细胞淋巴瘤的治疗,其各具特点,但在临床上也存在着不同程度的不良反应。由于B细胞淋巴瘤发病机制的复杂性及多样性,单靶点的PI3Kδ抑制剂疗效往往有限,且易产生耐药性,常需联合化疗或其他靶向药物以提升疗效。PI3Kδ抑制剂的未来发展趋势是开发高效低毒的新型抑制剂,或者探索与化疗、放疗及靶向药物等联合运用以达到更好的抗肿瘤效果同时减少不良反应的治疗方案。本文针对已上市和尚处于临床研究阶段的PI3Kδ抑制剂进行综述,重点围绕其作用特点、不良反应及联合用药方案。

     

2型糖尿病大鼠心肌PI3K/Akt/mTOR信号通路的改变及Sirt1的调控机制研究

目的检测Sirt1及PI3K/Akt/mTOR信号通路相关蛋白在糖尿病大鼠心肌及高糖培养的H9C2细胞中的表达变化,明确其在糖尿病心肌病发生发展中的作用。方法高脂饮食联合链脲佐菌素建立2型糖尿病大鼠模型,实验将大鼠分为糖尿病2周、4周、8周模型组和对照组,超声心动图检测大鼠心功能变化,Western blot检测大鼠心肌Sirt1、PI3K、Akt、mTOR、S6K1蛋白表达变化。将H9C2细胞分为正常对照组、DMSO组(78.12 mmol·L~(-1))、高糖(HG)组(33 mmol·L~(-1))、白藜芦醇(Res)组(20μmol·L~(-1))、尼克酰胺(Nam)组(40 mmol·L~(-1)),Western blot及qRT-PCR研究心肌细胞Sirt1、PI3K、Akt、mTOR、S6K1相关蛋白基因转录及表达,研究Sirt1对该信号通路的调控机制。结果在动物实验中,与2周DM大鼠比较,8周DM大鼠心肌Sirt1蛋白表达明显增加。2周模型组大鼠相对于正常对照组心肌PI3K、Akt、mTOR、S6K1表达明显增加,且S6K1表达4周模型组比2周模型组增加更明显,但8周表达降低。在高糖培养的H9C2细胞中,与对照组相比,高糖组Sirt1,PI3K,Akt,mTOR和S6K1表达明显增高。Nam处理组Sirt1表达明显降低,PI3K,Akt,mTOR和S6K1表达增高。Res处理组Sirt1表达明显增高,而PI3K,Akt,mTOR和S6K1表达降低。结论 Sirt1通过负调控PI3K/Akt/mTOR信号通路参与糖尿病心肌损伤,参与早期糖尿病心肌病的发生发展。     

用于肿瘤治疗的PI3K/mTOR双重抑制剂的研究进展

磷脂酰肌醇3-激酶（PBK）是细胞内重要的信号转导分子,在细胞存活、增殖和分化过程中起重要调节作用。且是磷脂酰肌醇3-激酶／蛋白激酶B／雷帕霉素靶蛋白信号转导通路的关键节点蛋白,与细胞周期、血管形成、肿瘤发生和侵袭的关系密切,现已证实PBKs是潜力巨大的药物治疗靶点,针对该通路的抑制剂近年来成为研究热点,抗肿瘤治疗前景看好。     

PI3K/AKT/mTOR信号通路抑制剂在宫颈癌治疗中的研究进展

宫颈癌是女性常见恶性肿瘤之一。针对局部晚期及复发转移的宫颈癌患者尚未有令人满意的治疗手段,因此探索和发展更有效的治疗方案具有重要的意义。PI3K/AKT/m TOR信号通路在人类子宫颈癌细胞的增殖、分化和凋亡中具有重要的调节作用,有希望成为开发宫颈癌治疗药物的新型靶标。综述了近年来PI3K/AKT/m TOR信号通路的单一及双重靶点抑制剂针对宫颈癌的临床前及临床研究情况,包括PI3K抑制剂(wortmannin、LY294002、吲哚-3-甲醇)、AKT抑制剂(SC-66、MK-2206、木黄酮、冬凌草甲素和雷公藤)、m TOR抑制剂(替西罗莫司和依维莫司)及双重靶点抑制剂(GSK2126458、BEZ235、BGT226、PF04691502、GDC-0980和PKI-587)等。     

Structure-based design of a novel series of potent, selective inhibitors of the class I phosphatidylinositol 3-kinases

A highly selective series of inhibitors of the class I phosphatidylinositol 3-kinases (PI3Ks) has been designed and synthesized. Starting from the dual PI3K/mTOR inhibitor 5, a structure-based approach was used to improve potency and selectivity, resulting in the identification of 54 as a potent inhibitor of the class I PI3Ks with excellent selectivity over mTOR, related phosphatidylinositol kinases, and a broad panel of protein kinases. Compound 54 demonstrated a robust PD-PK relationship inhibiting the PI3K/Akt pathway in vivo in a mouse model, and it potently inhibited tumor growth in a U-87 MG xenograft model with an activated PI3K/Akt pathway.     

Dual inhibitors of PI3K/mTOR or mTOR-selective inhibitors: which way shall we go?

The phosphatidylinositol-3-kinase (PI3K)/AKT/mTOR signaling pathway is a central regulator in cell proliferation, growth, and angiogenesis. Inhibition of this pathway therefore is a major strategy for cancer chemotherapy. In order to induce the maximal therapeutic outcome in cancer treatment, vertical inhibition of the PI3K/AKT/mTOR pathway or horizontal inhibition of PI3K/AKT/mTOR and other kinases has been reported. In this review, we discuss the drug design and clinical development of dual inhibitors of PI3K and mTOR as well as the mTOR-selective inhibitors, classified based on the mechanism of action and the chemical structures. Structural determinants for increasing selectivity toward PI3Kα or mTOR are revealed from the structure-activity relationship of the reported inhibitors. Current clinical development in combination therapy of inhibitors involving in the PI3K/AKT/mTOR pathway is also discussed.     

ATP-competitive inhibitors of mTOR: an update

mTOR (mammalian target of rapamycin) is a serine-threonine kinase belonging to the PI3K/Akt/mTOR signalling pathway that is involved in several cell functions, including growth, proliferation, apoptosis and autophagy. mTOR hyperactivation has been detected in several human cancers, thus representing, together with its upstream effectors, an important target for cancer therapy. mTOR exists in two different complexes in cells, mTORC1 and mTORC2 which could both be targeted by potential anticancer agents. Rapamycin, the selective and allosteric inhibitor of mTOR, inhibits the enzyme in mTORC1, but not in mTORC2. In the last few years a number of mTOR ATP-competitive inhibitors has been reported acting on mTOR in both complexes and possessing a more complete anticancer activity in comparison with that of rapamycin and its derivatives. mTOR shares high sequence homology in the hinge-region with PI3K that is a lipid kinase upstream to mTOR in the same signaling pathway; for this reason some compounds originally developed as PI3K inhibitors later showed to also target mTOR. As indicated by preclinical and clinical studies, compounds acting on more than one target could result in a better biological response and in enhanced therapeutic potential and also dual PI3K/mTOR inhibitors result of great interest as potential antitumor agents. This review mainly reports the recently discovered mTOR ATP-competitive inhibitors in terms of medicinal chemistry, classified by their chemical structures, focusing on SAR and modelling studies that led to the discovery of very potent and selective agents, such as AZD-8055, OSI-027 and INK128, already entered clinical trials, or WYE-132, Torin1 and others in preclinical studies. Also some examples of dual PI3K/mTOR inhibitors, including PI-103, GNE477, WJD008 and GSK2126458 are reported together with their biological and clinical data.     

A novel PI3K/mTOR dual inhibitor XH002 exhibited robust antitumor activity in NSCLC

Abstract

NSCLC is a worldwide challenge due to its high incidence and poor survival. PI3K-Akt-mTOR (PAM) pathway is one of the major pathways that mediate receptor tyrosine kinases (RTKs) signalling transduction. Aberration in PAM pathway is indicated correlating with poor prognosis of NSCLC. In this article, we highlighted a 2-amino-4-methylquinazoline derivative XH002 as PI3K/mTOR dual inhibitor with outstanding antitumor efficacy. Briefly, XH002 significantly repressed proliferation of PI3KCA mutant and/or P-S6RP, P-RAS40 high expressed NSCLC cells. In vitro, XH002 decreased the phosphorylation of PAM pathway proteins in a dose-dependent and time-dependent way. Further investigation indicated that the cancer cells repression by XH002 derived from inducing cell cycle arrest in G1 phase. Moreover, XH002 remarkably inhibited tumour growth of EGFR-TKIs resistant NCI-H1975 xenograft model by blocking PAM pathway. In conclusion, XH002 is a potent oral PI3K/mTOR dual inhibitor that possesses excellent antitumor efficacy against PIK3CA mutant NSCLC, including which resistant to EGFR-TKIs treatments.     

PI3K/Akt/mTOR通路在炎症相关疾病中分子机制研究进展

炎症是一种机体应对感染、组织损伤或者细胞应激的反应,并且可以通过修复机制恢复组织功能。炎症发生时会引起多条信号通路的激活,包括核转录因子-κB（NF-κB）通路、Janus激酶/信号转导与转录激活子（JAK/STAT）通路、丝裂原活化蛋白激酶（MAPK）通路以及磷脂酰肌醇-3-激酶/蛋白激酶B /雷帕霉素靶蛋白（PI3K/Akt/mTOR）通路等。本文综述了近年来磷脂酰肌醇-3-激酶/蛋白激酶B /雷帕霉素靶蛋白通路在炎症相关疾病中的分子作用机制,为研发以磷脂酰肌醇-3-激酶/蛋白激酶B /雷帕霉素靶蛋白为靶点的药物提供理论依据。     

PI3K/AKT/mTOR信号通路参与脊髓损伤后神经元自噬的研究进展

PI3K/AKT/mTOR信号通路是脊髓损伤后的一条经典的自噬途径,脊髓损伤后导致的神经元细胞凋亡、轴 突脱髓鞘和炎症反应等受 PI3K/AKT/mTOR 信号通路的调控,并和神经元自噬相关。介绍脊髓损伤后 PI3K/AKT/ mTOR信号通路在神经元自噬过程中的主要作用,为进一步研究脊髓损伤提供参考。