Natural product-based modulators of 4E-BP1 phosphorylation

基于天然产物的 4E-BP1 磷酸化调节剂

基本信息

批准号：
9889908
负责人：
QING-BAI SHE
金额：
$ 38.16万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9889908
关键词：
Antineoplastic Agents Binding Biological Assay CCI-779 Colorectal Cancer Complex Development Disease Disease Progression Drug Kinetics Drug resistance EIF4EBP1 gene FRAP1 gene Generations Genetic Genetic Translation Goals In Vitro Knowledge MEKs Malignant Neoplasms Maximum Tolerated Dose Mediating Messenger RNA Modeling Molecular Molecular Probes Mutation Naphthoquinones Natural Products Neoplasm Metastasis Oncogenes Oncogenic Oncoproteins PI3K/AKT PTEN gene Pathway interactions Patients Pharmaceutical Preparations Pharmacodynamics Pharmacology Pharmacotherapy Phosphorylation Phosphotransferases Production Property Protein Inhibition Proteins Proteomics Proto-Oncogene Proteins c-akt Ras/Raf Reactive Oxygen Species Reporter Research Resistance Ribosomes Signal Pathway Signal Transduction Structure Testing Therapeutic Therapeutic Index Toxic effect Translation Initiation Translational Regulation Translations Treatment Efficacy Work Xenograft procedure analog base cancer cell cancer therapy cell growth clinical efficacy colorectal cancer progression colorectal cancer treatment drug development effective therapy expectation in vitro Assay in vivo inhibitor/antagonist interest mTOR Inhibitor mTOR inhibition metastatic colorectal mouse model mutant novel novel strategies novel therapeutic intervention pharmacokinetics and pharmacodynamics pre-clinical prevent public health relevance targeted treatment tumor tumor growth tumor xenograft tumorigenesis upstream kinase

项目摘要

DESCRIPTION (provided by applicant): Metastatic colorectal cancer (CRC) is difficult to treat and patients have few long term effective therapeutic options. The aggressiveness of this disease is in part driven by the aberrant expression of oncoproteins. At the molecular level, cap-dependent translation of the precursor oncogenic mRNAs is frequently activated. Specifically this occurs via 4E-BP1 phosphorylation which, when not phosphorylated, functions as a mRNA translation repressor downstream from mTOR. We recently discovered that activated signaling via the PI3K/AKT and RAS/RAF/MEK/ERK pathways cooperate to promote CRC progression by convergent phosphorylation of 4E-BP1. Our work further demonstrated that 4E-BP1 phosphorylation-mediated oncogene translation functions as a critical node that integrates oncogenic signals of the AKT and ERK pathways for CRC tumorigenesis and metastasis. Moreover, we found that CRC resistance to upstream kinase targeted therapy is associated with incomplete inhibition of 4E-BP1 phosphorylation. Notably, genetic blockade of cap-dependent translation by a dominant active and non-phosphorylated 4E-BP1 mutant can effectively suppress tumor growth and metastasis in the mouse models of CRC. Our overarching hypothesis is that directly targeting 4E-BP1 phosphorylation- mediated oncogene translation represents a novel strategy for cancer drug development and therapy. Using a cap-dependent translation-based reporter assay, we recently identified naturally occurring pyranonaphthoquinones that act as selective inhibitors of 4E-BP1 phosphorylation in a manner that is mechanistically distinct to existing mTOR inhibitors. The primary goals of the proposed studies are to determine the fundamental mechanism of pyranonaphthoquinone-based inhibition of 4E-BP1 phosphorylation and identify optimized analogs with suitable in vitro and in vivo potency and selectivity. Cumulatively, the proposed studies offer high potential for the identification and development of structurally and functionally novel agents to target the translational control of CRC progression and metastasis with the potential to define new molecular probes and early stage leads for first-in-class targeted therapies to treat CRC.

描述（由申请人提供）：转移性结直肠癌（CRC）难以治疗，并且患者几乎没有长期有效的治疗选择，该疾病的侵袭性部分是由分子水平上癌蛋白的异常表达驱动的。前体致癌 mRNA 的依赖性翻译经常被激活，具体来说，这是通过 4E-BP1 磷酸化发生的，当 4E-BP1 未磷酸化时，我们最近发现，它充当 mTOR 下游的 mRNA 翻译抑制子。通过 PI3K/AKT 和 RAS/RAF/MEK/ERK 途径激活信号，通过 4E-BP1 的聚合磷酸化协同促进 CRC 进展，我们的工作进一步证明 4E-BP1 磷酸化介导的癌基因翻译作为整合的关键节点发挥作用。此外，我们发现 CRC 对上游激酶靶向治疗的耐药性与 AKT 和 ERK 通路的致癌信号有关。 4E-BP1 磷酸化的不完全抑制值得注意的是，显性活性和非磷酸化 4E-BP1 突变体对帽依赖性翻译的基因阻断可以有效抑制 CRC 小鼠模型中的肿瘤生长和转移。 4E-BP1 磷酸化介导的癌基因翻译代表了癌症药物开发和治疗的一种新策略，我们最近使用基于帽依赖性翻译的报告基因测定法鉴定了天然存在的癌基因翻译。吡喃萘醌作为 4E-BP1 磷酸化的选择性抑制剂，其机制在机制上与现有 mTOR 抑制剂不同。拟议研究的主要目标是确定基于吡喃萘醌的 4E-BP1 磷酸化抑制的基本机制，并确定优化的类似物。总的来说，所提出的研究具有适当的体外和体内效力和选择性，为结构和开发的鉴定和开发提供了巨大的潜力。功能新颖的药物，以CRC进展和转移的翻译控制为目标，有可能为治疗CRC的一流靶向疗法定义新的分子探针和早期先导药物。