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

• 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
• 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

 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（由申请人提供）：在美国，肺癌导致的男性和女性死亡人数比任何其他癌症都多。晚期发现疾病和不能有效地治疗这种恶性肿瘤的化疗是生存率低的主要原因。目前迫切需要开发新的分子靶向药物来治疗肺癌，尽管识别癌细胞特有的靶点一直具有挑战性。这一SBIR第一阶段应用基于PDEI Pharmaceuticals LLC开发的创新技术平台，该平台源于该公司发现磷酸二酯酶10（PDE 10）在肺癌中升高，对肺肿瘤细胞的存活和增殖至关重要。PDE 10在信号转导中起核心作用，并且是有吸引力的癌症靶标，因为它在外周组织中具有低表达水平，但在癌症期间被强烈诱导，由此抑制剂具有高功效和低毒性的潜力。从一个广泛的药物化学努力，开发新的PDE 10抑制剂，一系列的茚衍生物的合成，并发现在体外选择性抑制肺肿瘤细胞的生长。先导化合物MCI-020被鉴定为具有吸引人的口服生物利用度，并且与其他组织和血浆相比能够获得高的肺浓度。MCI-020在肺癌的原位小鼠模型中耐受良好且高度有效。由于MCI-020具有提高效力和靶标选择性的潜力，我们提出了以下先导化合物优化目标。目的1合成一系列与MCI-020化学结构相关的新型茚衍生物，并评价其体外抗癌活性和对PDE 10的选择性。目标2将通过确定药代动力学、组织分布和最大耐受剂量来评估衍生物的药物样性质，以选择先导化合物。目的3将确定先导化合物在肺癌原位小鼠模型中的功效和毒性，并将使用来自小鼠模型的组织确认作用机制。我们预计该项目将产生临床候选药物，并将进入II期申请，涉及GMP规模放大合成和GLP毒性试验，以支持人体临床试验的IND申请。