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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：
9247152
负责人：
QING-BAI SHE
金额：
$ 39.57万
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 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9247152
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 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 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 pre-clinical prevent public health relevance targeted treatment tumor tumor growth tumor progression 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，患者几乎没有长期有效的治疗选择。这种疾病的侵袭性部分是由癌蛋白的异常表达驱动的。在分子水平上，前体致癌mRNA的帽依赖性翻译经常被激活。具体而言，这通过4 E-BP 1磷酸化发生，当不磷酸化时，其作为mTOR下游的mRNA翻译阻遏物起作用。我们最近发现，通过PI 3 K/AKT和RAS/RAF/MEK/ERK途径激活的信号通过4 E-BP 1的会聚磷酸化协同促进CRC进展。我们的工作进一步证明了4 E-BP 1磷酸化介导的癌基因翻译作为一个关键节点，整合了CRC肿瘤发生和转移的AKT和ERK通路的致癌信号。此外，我们发现CRC对上游激酶靶向治疗的抗性与4 E-BP 1磷酸化的不完全抑制有关。值得注意的是，通过显性活性和非磷酸化的4 E-BP 1突变体对帽依赖性翻译的遗传阻断可以有效地抑制CRC小鼠模型中的肿瘤生长和转移。我们的总体假设是，直接靶向4 E-BP 1磷酸化介导的癌基因翻译代表了癌症药物开发和治疗的新策略。使用基于帽依赖性抑制的报告基因测定，我们最近鉴定了天然存在的吡喃萘醌，其以与现有mTOR抑制剂在机制上不同的方式作为4 E-BP 1磷酸化的选择性抑制剂。提出的研究的主要目标是确定基于吡喃萘醌的4 E-BP 1磷酸化抑制的基本机制，并鉴定具有合适的体外和体内效力和选择性的优化类似物。总的来说，拟议的研究为鉴定和开发结构和功能新颖的药物提供了很大的潜力，以靶向CRC进展和转移的翻译控制，并有可能定义新的分子探针和早期线索，用于治疗CRC的一流靶向治疗。