Phosphodiesterase 10A, a novel target for lung cancer chemoprevention

磷酸二酯酶10A，肺癌化学预防的新靶点

基本信息

批准号：
9198369
负责人：
Gary A Piazza
金额：
$ 34.66万
依托单位：
UNIVERSITY OF SOUTH ALABAMA
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：
2016-07-15 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9198369
关键词：
Adverse effects Antineoplastic Agents Cardiovascular system Cell Line Cell Proliferation Cell Survival Cell physiology Cessation of life Chemicals Chemoprevention Clinic Clinical Clinical Research Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Colon Carcinoma Colonic Neoplasms Cyclic GMP Cyclic GMP-Dependent Protein Kinases Cyclin D1 Development Disease Drug Kinetics Drug Targeting Enzymes Epidemiologic Studies Epithelial Epithelial Cells Evaluation Genes Health Hepatotoxicity Human Human Cell Line Image Implant Incidence Individual Isoenzymes Kidney Knock-out Lead Lung Lung Neoplasms Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of prostate Malignant neoplasm of urinary bladder Measures Mediating Mesenchymal Molecular Molecular Models Molecular Target Mus Non-Steroidal Anti-Inflammatory Agents Oncogenic Oral Oral Administration Patients Pharmaceutical Preparations Phase Phase III Clinical Trials Plasma Preclinical Drug Development Prevention Property Prostaglandin-Endoperoxide Synthase Prostaglandins Proteins Rattus Recombinants Reporting Research Personnel Risk Rodent Model Role Safety Series Signal Transduction Small Interfering RNA Specimen Staging Structure Sulfones Sulindac Sulindac Sulfide Sulindac Sulfone Testing Tissues Toxic effect Translating Tumor Cell Line Ubiquitin Validation abstracting analog base beta catenin cancer chemoprevention cancer therapy cancer type cell growth cell motility cyclooxygenase 1 cyclooxygenase 2 docetaxel efficacy testing gastrointestinal genetic regulatory protein improved in vivo inhibitor/antagonist knock-down lung tumorigenesis malignant breast neoplasm molecular modeling mouse model neoplastic cell novel novel anticancer drug novel therapeutics overexpression phosphodiesterase IV phosphodiesterase V phosphoric diester hydrolase preclinical study small molecule inhibitor survivin tumorigenesis

项目摘要

Abstract Preclinical, clinical and epidemiological studies provide compelling evidence that nonsteroidal anti-inflammatory drugs (NSAIDs) have antineoplastic activity and significantly reduce the incidence and risk of death from multiple cancer types, including lung cancer. Unfortunately, the long-term use of NSAIDs for chemoprevention and their potential application for therapy are not recommended because of the risk of potentially fatal side-effects resulting from cyclooxygenase (COX) inhibition and the suppression of physiologically important prostaglandins. However, numerous investigators have concluded that the pharmacological basis for their antineoplastic activity may not require COX inhibition, which suggests the feasibility of developing safer and more efficacious non-COX inhibitory derivatives for cancer by targeting the underlying mechanism. We have extensively studied the mechanism by which the NSAID, sulindac inhibits tumor cell growth and have reported that this activity results from cyclic guanosine monophosphate phosphodiesterase (cGMP PDE) inhibition and the activation of cGMP/protein kinase G signaling to suppress oncogenic β-catenin/Tcf-transcriptional activity and the synthesis of key proteins, such as cyclin D1 and survivin that drive tumor cell proliferation and survival. Here we show that the cGMP degrading PDE isozyme, PDE10A is a critically important target of sulindac that is elevated in lung tumors and essential for lung tumor cell growth. Guided by molecular modeling using the crystal structure of PDE10, we synthesized a novel series of sulindac derivatives that potently and selectively inhibit lung tumor cell growth without inhibiting COX-1 or COX-2. These compounds have attractive drug-like properties whereby high lung concentrations relative to plasma and other tissues can be safely achieved by oral administration. A lead compound, MCI-048 was identified that displays strong antitumor activity in an orthotopic mouse model of lung cancer. Further analog development to identify a preclinical drug development candidate and studies to better define the role of PDE10 in lung cancer are therefore urgently needed. The following aims are proposed: 1) synthesize a novel series of sulindac derivatives to improve potency and selectivity, 2) evaluate PDE10 and lung tumor cell growth inhibitory activity of sulindac derivatives, 3) evaluate antitumor activity of sulindac derivatives in mouse models of lung cancer, and 4) further define the role of PDE10 in lung cancer. The focus of this project on the development of novel anticancer drugs and target validation for chemoprevention or therapy have the potential to impact individuals at risk of developing lung cancer as well as patients with advanced stage malignant disease.

抽象的临床前，临床和流行病学研究提供了令人信服的证据表明非甾体类抗炎药（NSAID）具有抗肿瘤活性，并且显着减少多种癌症（包括肺癌）的事件和死亡风险。不幸的是，NSAID用于化学预防及其潜在应用不建议治疗，因为导致潜在致命副作用的风险从环氧合酶（COX）抑制和物理上重要的抑制前列腺素。但是，许多调查人员得出的结论是药物其抗塑性活性的基础可能不需要Cox抑制作用，这表明通过为癌症开发更安全，更有效的非Cox抑制衍生物的可行性针对基本机制。我们已经广泛研究了 NSAID，Sulindac抑制了肿瘤细胞的生长，并报告了这种活性是由环状引起的鸟苷单磷酸磷酸二酯酶（CGMP PDE）抑制和激活 CGMP/蛋白激酶G信号传导以抑制致癌β-catenin/TCF转录活性以及关键蛋白的合成，例如驱动肿瘤细胞的Cyclin D1和Survivin 增殖和生存。在这里，我们证明CGMP降解PDE同工酶，PDE10A是一个苏氏菌的至关重要的靶标的肺部肿瘤升高，对肺部肿瘤必不可少细胞生长。通过使用PDE10的晶体结构进行分子建模的指导，我们合成了一系列新型的Sulindac衍生物，潜在和选择性地抑制肺部肿瘤细胞生长不抑制COX-1或COX-2。这些化合物具有吸引人的药物样特性因此，可以安全地实现相对于血浆和其他组织的高肺浓度通过口服给药。鉴定出铅化合物MCI-048，显示出强抗肿瘤在肺癌的原位小鼠模型中的活性。进一步的模拟发展以确定临床前药物开发候选和研究以更好地定义PDE10在肺中的作用因此，迫切需要癌症。提出了以下目的：1）合成小说一系列的苏莱达克衍生物以提高效力和选择性，2）评估PDE10和肺硫酸衍生物的肿瘤细胞生长抑制活性，3）评估抗肿瘤活性在肺癌小鼠模型中的苏丹衍生物，4）进一步定义了PDE10在肺癌。该项目的重点是新型抗癌药物和靶标的开发化学预防或治疗的验证有可能影响个人发展肺癌以及晚期恶性疾病的患者。