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

 描述(申请人提供)：在美国，肺癌导致的男性和女性死亡人数超过任何其他癌症。发现疾病较晚，不能有效地用化疗治疗这种恶性肿瘤是存活率低的主要原因。医学上迫切需要开发治疗肺癌的新的分子靶向药物，尽管识别癌细胞特有的靶点一直是一项挑战。这一阶段的SBIR应用是基于PDEi PharmPharmticals LLC正在开发的创新技术平台，该平台源于该公司发现肺癌中磷酸二酯酶10(PDE10)升高，对肺肿瘤细胞的生存和增殖至关重要。PDE10在信号转导中发挥核心作用，是一个有吸引力的肿瘤靶点，因为它在外周组织中表达水平低，但在癌症过程中被强烈诱导，因此抑制剂具有高效和低毒的潜力。在开发新型PDE10抑制剂的广泛药物化学努力的基础上，合成了一系列吲哚类化合物，并发现它们在体外具有选择性地抑制肺肿瘤细胞的生长。与其他组织和血浆相比，先导化合物MCI-020被证实具有诱人的口服生物利用度和获得高肺浓度的能力。在小鼠原位肺癌模型中，MCI-020耐受性好，疗效高。由于MCI-020具有提高药效和靶向选择性的潜力，我们提出了以下铅优化目标。目的1将合成一系列与MCI-020化学相关的新型吲哚类化合物，并将在体外评价PDE10的抗癌活性和选择性。目的2将通过测定药物动力学、组织分布和选择先导化合物的最大耐受量来评估这些衍生物的类药物性质。目的3将在原位小鼠肺癌模型中确定先导化合物的有效性和毒性，并将利用小鼠模型的组织来证实其作用机制。我们预计这一项目将产生一个临床候选项目，该项目将进入第二阶段应用，包括GMP扩大合成和GLP毒性测试，以支持IND应用于人体临床试验。

 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.