Novel AKT PH domain inhibitors to prevent skin cancer
新型 AKT PH 域抑制剂可预防皮肤癌
基本信息
- 批准号:7937893
- 负责人:
- 金额:$ 7.28万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-09-24 至 2012-08-31
- 项目状态:已结题
- 来源:
- 关键词:1-Phosphatidylinositol 3-KinaseActinic keratosisAnimal ModelApoptosisApplications GrantsAreaBasal cell carcinomaBindingBiological MarkersCancer ModelCancer cell lineCell ProliferationCell SurvivalCell membraneCell modelCellsChemopreventionChemopreventive AgentChronicClinicalComputer SimulationDataDetectionExhibitsGrowthHealthHumanHyperplasiaIn VitroLipid BindingMEKsMalignant NeoplasmsMeasuresMolecularMolecular TargetMusMutationPH DomainPTEN genePathway interactionsPhorbol EstersPreventionPrevention approachPrevention strategyPrimary PreventionProtective ClothingProtein IsoformsProtein-Serine-Threonine KinasesProto-Oncogene Proteins c-aktRiskRoleSignal PathwaySignal TransductionSkinSkin CancerSkin CarcinogenesisSkin CarcinomaSkin NeoplasmsSquamous cell carcinomaStagingStratified EpitheliumStratum BasaleSun ExposureSunscreening AgentsTestingThe SunTopical applicationTumor Suppressor ProteinsUltraviolet RaysUnited StatesWorkXenograft ModelXenograft procedurebasecancer cellcancer diagnosiscarcinogenesisin vivoinhibitor/antagonistkeratinocytemelanomamouse modelnoveloverexpressionplatelet protein P47pre-clinicalpreventskin cancer preventionsmall hairpin RNAsuccesstherapeutic targettumortumor progression
项目摘要
DESCRIPTION (provided by applicant):
Recent advances in our understanding of the molecular basis of carcinogenesis have led to the identification of potential molecular targets that could be used to prevent the progression of early skin cancer. While a number of agents have been tested in skin cancer prevention studies, very few have been directed against molecular targets known to be involved in skin carcinogenesis. AKT (protein kinase B) is a pleckstrin homology (PH) lipid binding domain containing, serine/threonine kinase that is a key component of the phosphatidylinositol-3-kinase (PI3K) cell survival signaling pathway that is activated in many skin cancers. AKT activity increases in parallel with the phorbol ester induced promotion stages of mouse skin carcinogenesis while constitutively active AKT in the basal layer of the mouse stratified epithelia induces an increase in epidermal proliferation leading to alterations in epidermal differentiation and hyperplasia. Ultraviolet light B (UVB) is capable of inducing AKT activation and xenografted cells that overexpress myristoylated-AKT develop faster and form bigger tumors compared to cells that express normal levels of AKT. Finally loss of the tumor suppressor, PTEN which leads to the constitutive activation of AKT occurs 10-30% of melanoma frequently concurrent with activating mutations of B-Raf. Taken together, these data provide evidence for a critical role for AKT in skin carcinogenesis and skin tumor progression. Thus, AKT represents an attractive molecular target for skin cancer prevention. We have developed a novel inhibitor of AKT (PH4) that binds to the pleckstrin homology domain of AKT thus preventing its binding to PI-(3,4,5)P3 in the plasma membrane and subsequent AKT activation. PH4 inhibits AKT activity at low micromolar concentrations and exhibits good systemic anti-tumor activity in xenografts models. Recently, we have found that PH4 is able to prevent UVB-induced AKT activation and expression in HaCaT keratinocytes cells and in the skin of the SKH-1 mouse model. Moreover, the compound is lipophilic and we have found that it readily penetrates the skin in mice when applied topically, and significantly decreases AKT levels. Thus, the hypothesis upon which our work is based on is that the topical use of a novel lipophilic AKT inhibitor will provide an effective chemotherapeutic strategy for the prevention of non-melanoma skin cancers. The objectives of the proposed studies are: 1) to investigate the role of AKT and its isoforms in NMSCs, 2) to investigate the activity of the novel AKT inhibitor PH4 in cellular models of skin cancer and 3) to investigate the chemopreventive effects of PH4 in the UVB-induced skin SKH-1 mouse model.
描述(由申请人提供):
我们对致癌分子基础的理解的最新进展导致了可用于预防早期皮肤癌进展的潜在分子靶点的识别。虽然许多药物已在皮肤癌预防研究中进行了测试,但很少有药物针对已知参与皮肤癌发生的分子靶标。 AKT(蛋白激酶 B)是一种含有丝氨酸/苏氨酸激酶的 pleckstrin 同源 (PH) 脂质结合域,是磷脂酰肌醇 3 激酶 (PI3K) 细胞存活信号通路的关键组成部分,在许多皮肤癌中被激活。 AKT 活性的增加与佛波酯诱导的小鼠皮肤癌发生的促进阶段平行,而小鼠复层上皮基底层中的组成型活性 AKT 诱导表皮增殖增加,导致表皮分化和增生的改变。紫外线 B (UVB) 能够诱导 AKT 激活,与表达正常水平 AKT 的细胞相比,过度表达肉豆蔻酰化 AKT 的异种移植细胞发育更快并形成更大的肿瘤。最后,10-30% 的黑色素瘤中,肿瘤抑制因子 PTEN 的缺失导致 AKT 的组成性激活,通常与 B-Raf 的激活突变同时发生。总而言之,这些数据提供了 AKT 在皮肤癌发生和皮肤肿瘤进展中发挥关键作用的证据。因此,AKT 代表了预防皮肤癌的一个有吸引力的分子靶点。我们开发了一种新型 AKT 抑制剂 (PH4),它与 AKT 的 pleckstrin 同源结构域结合,从而阻止其与质膜中的 PI-(3,4,5)P3 结合以及随后的 AKT 激活。 PH4 在低微摩尔浓度下抑制 AKT 活性,并在异种移植模型中表现出良好的全身抗肿瘤活性。最近,我们发现 PH4 能够阻止 UVB 诱导的 HaCaT 角质形成细胞和 SKH-1 小鼠模型皮肤中的 AKT 激活和表达。此外,该化合物具有亲脂性,我们发现局部使用时它很容易渗透小鼠皮肤,并显着降低 AKT 水平。因此,我们的工作所基于的假设是,局部使用新型亲脂性 AKT 抑制剂将为预防非黑色素瘤皮肤癌提供有效的化疗策略。拟议研究的目的是:1) 研究 AKT 及其亚型在 NMSC 中的作用,2) 研究新型 AKT 抑制剂 PH4 在皮肤癌细胞模型中的活性,3) 研究 PH4 的化学预防作用在 UVB 诱导的皮肤 SKH-1 小鼠模型中。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Novel inhibitors of AKT: assessment of a different approach targeting the pleckstrin homology domain.
AKT 的新型抑制剂:评估针对 pleckstrin 同源结构域的不同方法。
- DOI:
- 发表时间:2011
- 期刊:
- 影响因子:4.1
- 作者:Meuillet; E J
- 通讯作者:E J
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Emmanuelle Joelle Meuillet其他文献
Emmanuelle Joelle Meuillet的其他文献
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Novel AKT PH domain inhibitors to prevent skin cancer
新型 AKT PH 域抑制剂可预防皮肤癌
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