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：
9050804
负责人：
QING-BAI SHE
金额：
$ 39.12万
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/9050804
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 PI3K/AKT PTEN gene Pathway interactions Patients Pharmaceutical Preparations Pharmacodynamics Pharmacotherapy Phosphorylation Phosphotransferases Production Property Protein Inhibition Proteins Proteomics Proto-Oncogene Proteins c-akt Reactive Oxygen Species Reporter Research Resistance Signal Pathway Signal Transduction Staging Testing Therapeutic Therapeutic Index Toxic effect Translation Initiation Translational Regulation Translations 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（由适用提供）：转移性结直肠癌（CRC）很难治疗，患者几乎没有长期有效的治疗选择。这种疾病的侵略性部分是由癌蛋白异常表达驱动的。在分子水平上，经常激活前体致癌mRNA的帽依赖性翻译。具体而言，这是通过4E-BP1磷酸化发生的，如果未磷酸化，则可以作为MTOR下游的mRNA翻译复制品。我们最近发现，通过PI3K/AKT和RAS/RAF/MEK/ERK途径激活信号，以通过4E-BP1的收敛磷酸化来促进CRC进展。我们的工作进一步表明，4E-BP1磷酸化介导的癌基因翻译是一种临界节点，它整合了CRC肿瘤发生和转移的AKT和ERK途径的致癌信号。此外，我们发现CRC对上游激酶靶向疗法的耐药性与4E-BP1磷酸化的不完全抑制有关。值得注意的是，在CRC的小鼠模型中，通过主动活性和非磷酸化的4E-BP1突变体对帽依赖性翻译的遗传阻断可以有效地抑制肿瘤的生长和转移。我们的总体假设是，直接针对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新型策略。我们使用基于CAP依赖性翻译的记者测定法，我们最近鉴定出天然存在的吡喃富喹酮，这些喹酮可作为4E-BP1磷酸化的选择性抑制剂，其方式与现有的MTOR抑制剂在机械上不同。拟议的研究的主要目标是确定基于4E-BP1磷酸化的基于吡喃富烯酮的抑制剂的基本机制，并鉴定具有适合体外和体内效力和选择性的优化类似物。累积地，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高的潜力，以靶向CRC进展和转移的转化控制，具有定义新分子问题的潜力，并为治疗CRC的第一类靶向疗法提供了早期阶段。