A novel phosphodiesterase isozyme target and class of inhibitors for lung cancer

一种新型磷酸二酯酶同工酶靶点和一类肺癌抑制剂

基本信息

批准号：
8903904
负责人：
Joshua Canzoneri
金额：
$ 22.49万
依托单位：
ADT PHARMACEUTICALS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-09 至 2016-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8903904
关键词：
A549 Adenocarcinoma Cell Alabama Apoptosis Autopsy Biological Biological Assay Biological Availability Blood - brain barrier anatomy Brain Cancer Etiology Cancer cell line Cell Line Cell Proliferation Cell Survival Cells Cessation of life Characteristics Chemicals Chemistry Clinical Clinical Trials Colon Carcinoma Cyclic GMP Cyclin D1 Detection Development Disease Dose Drug Kinetics Drug Targeting Drug or chemical Tissue Distribution Ensure Enzyme Kinetics Enzymes Epithelial Cells Goals Growth Histopathology Human Image Immunohistochemistry In Vitro Indenes Institutes Isoenzymes Lead Luciferases Lung Lung Adenocarcinoma Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of prostate Measures Medical Metabolic Molecular Models Molecular Target Monitor Mus Oncogenic Oral Oral Administration Organ Patients Peripheral Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Phase Phenotype Plasma Play Proliferation Marker Property Race Respiratory physiology Role Series Serum Signal Transduction Small Business Innovation Research Grant Structure Structure of parenchyma of lung Structure-Activity Relationship Survival Rate Tissues Toxic effect Toxicity Tests Treatment Protocols Tumor Cell Line United States Universities Weight Gain Woman absorption analog anticancer activity base beta catenin cancer cell caspase-3 cell growth chemotherapy design dosage drug candidate expression vector improved in vivo inhibitor/antagonist innovative technologies malignant breast neoplasm men molecular modeling mouse model neoplastic cell novel phosphoric diester hydrolase pre-clinical programs prototype public health relevance scaffold scale up screening stem survivin treatment effect tumor tumor growth vasodilator-stimulated phosphoprotein

项目摘要

DESCRIPTION (provided by applicant): Lung cancer causes more deaths in men and women than any other cancer in the United States. Late detection of disease and inability to effectively treat this malignancy with chemotherapy are the main reasons for low survival rates. There is an urgent medical need to develop new molecularly targeted drugs for treating lung cancer, although it has been challenging to identify targets that are unique to cancer cells. This phase 1 SBIR application is based on an innovative technology platform being developed by PDEi Pharmaceuticals LLC stemming from the company's discovery that phosphodiesterase 10 (PDE10) is elevated in lung cancer and essential for the survival and proliferation of lung tumor cells. PDE10 plays a central role in signal transduction and is an attractive cancer target because it has low expression levels in peripheral tissues, but is strongly induced during cancer, whereby inhibitors have potential for high efficacy and low toxicity. From an extensive medicinal chemistry effort to develop novel PDE10 inhibitors, a series of indene derivatives were synthesized and found to selectively inhibit lung tumor cell growth in vitro. A lead compound, MCI-020 was identified with attractive oral bioavailability and ability to obtain high lung concentrations compared to other tissues and plasma. MCI-020 was well tolerated and highly efficacious in an orthotopic mouse model of lung cancer. Because of the potential to improve potency and target selectivity of MCI-020, we propose the following aims for lead optimization. Aim 1 will synthesize a series of novel indene derivatives chemically related to MCI-020 and will evaluate in vitro anticancer activity and selectivity for PDE10. Aim 2 will assess drug-like properties of the derivatives by determining pharmacokinetics, tissue distribution, and maximum tolerated dosage to select a lead compound. Aim 3 will determine efficacy and toxicity of the lead compound in an orthotopic mouse model of lung cancer and will confirm mechanism of action using tissues from the mouse model. We anticipate a clinical candidate will result from this project that will be advanced to a phase II application involving GMP scale-up synthesis and GLP toxicity testing in support of an IND application for human clinical trials.

描述（由适用提供）：与美国任何其他癌症相比，肺癌导致男性和女性死亡更多。疾病的晚期发现和无法有效治疗这种恶性肿瘤是较低存活率的主要原因。迫切需要开发新的分子靶向药物来治疗肺癌，尽管挑战是要确定癌细胞独有的靶标。该第1阶段的SBIR应用是基于由PDEI Pharmaceuticals LLC开发的创新技术平台，该平台源于该公司的发现，即在肺癌中磷酸二酯酶10（PDE10）升高，对于肺部肿瘤细胞的生存和增殖至关重要。 PDE10在信号转导中起着核心作用，并且是一个有吸引力的癌症靶标，因为它在外周组织中的表达水平较低，但在癌症期间强烈诱导，因此抑制剂具有高效率和低毒性的可能性。从广泛的医学化学工作中开发新型PDE10抑制剂，合成了一系列的吲哚衍生物，并发现在体外抑制肺肿瘤细胞的生长。与其他时间和等离子体相比，铅化合物MCI-020具有吸引人的口服生物利用度和获得高肺浓度的能力。 MCI-020的耐受性很好，高度目标1将合成一系列与MCI-020化学相关的新型indene衍生物，并将评估PDE10的体外抗癌活性和选择性。 AIM 2通过确定药代动力学，组织分布和最大耐受剂量以选择铅化合物来评估衍生物的药物样性能。 AIM 3将在肺癌的原位小鼠模型中确定铅化合物的有效性和毒性，并使用小鼠模型的时机确认作用机理。我们预计，该项目将导致临床候选者，该项目将推进II期应用，涉及GMP缩放合成和GLP毒性测试，以支持人类临床试验的IND应用。