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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.

摘要