Development of Small Molecule Crm-1 Inhibitor for Pancreatic Cancer Therapy

开发用于治疗胰腺癌的小分子 Crm-1 抑制剂

• 批准号: 8355966
• 负责人: Ramzi M. Mohammad
• 金额: $ 19.84万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-15 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8355966
• 关键词: American; Animals; Apoptosis; Apoptotic; Automobile Driving; Binding; Biological Factors; Cancer cell line; Cell Line; Cell Nucleus; Cells; Chromosomes; Chromosomes, Human, Pair 4; Clinical; Clinical Trials; Colon Carcinoma; Cyclic AMP-Dependent Protein Kinases; Cytoplasm; Development; Disease; Disease Management; Dose; Down-Regulation; Drug Delivery Systems; Drug Design; Drug Kinetics; Ductal Epithelial Cell; Event; Exclusion; Exportins; Failure; Goals; Growth; Human; Importins; Inhibitory Concentration 50; Leucine; Link; Lymphocyte; Lymphoma; Maintenance; Malignant Neoplasms; Malignant neoplasm of pancreas; Malignant neoplasm of prostate; Mediating; Normal Cell; Nuclear; Nuclear Export; Oral Administration; PAWR protein; Pancreas; Patients; Peripheral; Pharmaceutical Preparations; Phosphorylation; Physiology; Process; Property; Prostate; Protein Export Pathway; Proteins; Resistance; Short Interspersed Nucleotide Elements; Structure; Testing; Therapeutic; Therapeutic Agents; Time; Toxic effect; Tumor Suppressor Proteins; Tumor Tissue; Xenograft Model; Xenograft procedure; base; cancer cell; cancer therapy; chemotherapy; design; in vivo; inhibitor/antagonist; innovation; killings; leptomycin B; malignant breast neoplasm; member; molecular marker; mortality; mouse model; novel; novel therapeutics; nucleocytoplasmic transport; outcome forecast; pancreatic cancer cells; receptor; response; small molecule; stem; success; therapeutic target; tumor; tumor growth

DESCRIPTION (provided by applicant): Pancreatic cancer is a deadly disease that takes two American lives every 30 minutes (annual mortality >33,000). Failure of standard chemotherapies and newly developed targeted therapies has stagnated any improvement on the overall dismal survival (<5%) indicating that newer strategies for the management of this disease are urgently needed. In line with the goals of this RFA i.e. to identify potential molecula targets, and to test new therapeutic strategies, we intend to investigate the therapeutic potential of targeting CRM-1 (chromosome region maintenance 1) by our newly developed selective inhibitors of nuclear export (SINE) in pancreatic cancer. CRM-1 is a member of the importin superfamily of nuclear transport receptors, recognizing proteins bearing a leucine-rich nuclear export sequence (NES) and is the major receptor for the export of proteins out of the nucleus. Among the target of CRM-1 is the tumor suppressor protein (TSP) prostate apoptosis response-4 (Par-4). Earlier we had proposed Par-4 as a potential therapeutic target in pancreatic cancer since downregulation of this TSP has been directly linked to poor overall survival. Nuclear exclusion of Par-4 by CRM-1 renders the cancer cells resistant to apoptosis. Our preliminary findings demonstrate that SINE (KPT-185 and clinical candidate KPT-251) can lock Par-4 in pancreatic cancer cell nucleus by inhibiting CRM-1 that leads to cancer cell selective apoptosis and anti-tumor effects. To our surprise normal cells did not respond SINEs and this emerges to be mechanistically co-related to low Par-4 expression and insignificant Par-4 phosphorylation due to low protein kinase A (PKA). Hence we hypothesize that targeted inhibition of CRM-1 is an attractive strategy to guide TSPs (specifically Par-4) in the nucleus, inducing pancreatic cancer specific apoptosis. Based on our provocative initial findings and to test our hypothesis we propose 1. To establish whether there is a direct relationship between Par-4 nuclear localization and growth inhibitory and apoptosis inducing activity of KPT-185 and KPT-251 in a panel of pancreatic cancer cell lines with differential PKA and Par-4 expression and establish whether knockdown of PKA can cause resistance to KPT-mediated killing through Par-4 and other mechanisms. 2. Assess the in vivo efficacy of KPT- 251 (clinical candidate at MTD) in animal xenograft mice models developed from pancreatic cell lines with differential Par-4 expression (high Par-4 PKA vs low Par-4 PKA). Impact: CRM-1 is a druggable target in pancreatic cancer, however, currently there is no existing drug targeting this detrimental nuclear exporter. Earlier attempts to develop CRM-1 inhibitor were not successful as exemplified by the failure of the natural product Leptomycin B in a single clinical trial due to severe toxicity. Sinc then the field has not witnessed any serious attempts to develop newer classes of CRM-1 inhibitors that could be used clinically for the treatment of pancreatic cancer. Our newly developed KPT-SINE's are highly specific, orally active drugs with excellent pharmacokinetic parameters and hold promise against deadly pancreatic cancer. PUBLIC HEALTH RELEVANCE: CRM-1 is a druggable target in pancreatic cancer, however, currently there is no existing drug targeting this detrimental nuclear exporter. Earlier attempts t develop CRM-1 inhibitor were not successful as exemplified by the failure of the natural product Leptomycin B in a single clinical trial due to severe toxicity. Since then the field has not witnessed any serious attempts to develop newer classes of CRM-1 inhibitors that could be used clinically for the treatment of pancreatic cancer. Our newly developed KPT-SINE's are highly specific, orally active drugs with excellent pharmacokinetic parameters and hold promise against deadly pancreatic cancer.

描述（申请人提供）：胰腺癌是一种致命的疾病，每30分钟就有两名美国人死亡（年死亡率> 33，000）。标准化疗和新开发的靶向治疗的失败阻碍了总体生存率的改善（<5%），这表明迫切需要管理这种疾病的新策略。根据本RFA的目标，即确定潜在的分子靶点，并测试新的治疗策略，我们打算研究治疗潜力 通过我们新开发的选择性核输出抑制剂（SINE）靶向CRM-1（染色体区域维持1）治疗胰腺癌。CRM-1是核转运受体的输入素超家族的成员，识别带有富含亮氨酸的核输出序列（内斯）的蛋白质，并且是将蛋白质输出到细胞核外的主要受体。CRM-1的靶标之一是肿瘤抑制蛋白（TSP）前列腺凋亡反应-4（Par-4）。早些时候，我们已经提出Par-4作为胰腺癌的潜在治疗靶点，因为该TSP的下调与总体生存率差直接相关。CRM-1对Par-4的核排斥使癌细胞对凋亡具有抗性。我们的初步研究结果表明，SINE（KPT-185和临床候选KPT-251）可以通过抑制CRM-1将Par-4锁定在胰腺癌细胞核中，从而导致癌细胞选择性凋亡和抗肿瘤作用。令我们惊讶的是，正常细胞对西内斯没有反应，这与低蛋白激酶A（PKA）导致的低Par-4表达和不显著的Par-4磷酸化在机制上相关。因此，我们假设CRM-1的靶向抑制是在细胞核中引导TSP（特别是Par-4），诱导胰腺癌特异性细胞凋亡的有吸引力的策略。基于我们的挑衅性的初步研究结果，并测试我们的假设，我们提出1。在一组PKA和Par-4表达差异的胰腺癌细胞系中，确定Par-4核定位与KPT-185和KPT-251的生长抑制和凋亡诱导活性之间是否存在直接关系，并确定PKA敲低是否可通过Par-4和其他机制导致对KPT介导的杀伤的抗性。2.评估KPT- 251（MTD的临床候选药物）在动物异种移植小鼠模型中的体内疗效，该模型由具有差异Par-4表达（高Par-4 PKA vs低Par-4 PKA）的胰腺细胞系开发。影响：CRM-1是胰腺癌中的一个可药物靶点，然而，目前还没有针对这种有害的核输出者的药物。早期开发CRM-1抑制剂的尝试并不成功，如天然产物Leptomycin B在单一临床试验中由于严重毒性而失败所例证的。此后，该领域还没有看到任何认真的尝试来开发可用于临床治疗胰腺癌的新型CRM-1抑制剂。我们新开发的KPT-SINE是高度特异性的口服活性药物，具有出色的药代动力学参数，有望对抗致命的胰腺癌。 公共卫生关系：CRM-1是胰腺癌中的一个药物靶点，然而，目前还没有针对这种有害的核输出者的药物。早期开发CRM-1抑制剂的尝试并不成功，例如天然产物Leptomycin B在单一临床试验中由于严重毒性而失败。从那时起，该领域没有看到任何认真的尝试来开发可用于临床治疗胰腺癌的新型CRM-1抑制剂。我们新开发的KPT-SINE是高度特异性的口服活性药物，具有出色的药代动力学参数，有望对抗致命的胰腺癌。