cardiac neoglycosides as cancer drugs

强心新苷类作为抗癌药物

• 批准号: 7393031
• 负责人: charles r hutchinson
• 金额: $ 16.32万
• 依托单位: CENTROSE, LLC
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-27 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7393031
• 关键词: Actins; Animals; Antineoplastic Agents; Apoptosis; Area; Arrhythmia; Back; Belief; Biological; Biological Assay; Biological Factors; Breast Cancer Treatment; Calcium ion; Cancer cell line; Cardenolides; Cardiac; Cardiac Glycosides; Cardiac Myocytes; Cardiotoxicity; Cells; Chemicals; Chemistry; Clinical; Clinical Trials; Congestive Heart Failure; Contractor; Development; Digitoxigenin; Digitoxin; Digoxin; Evaluation; Exhibits; Funding; Glycosides; Goals; Hexoses; Human; Ions; Laboratories; Lead; Legal patent; Libraries; Licensing; Malignant Neoplasms; Mediating; Membrane; Muscle function; Myocardial; Myocardium; Na(+)-K(+)-Exchanging ATPase; National Cancer Institute; Non-Small-Cell Lung Carcinoma; Other Finding; Pentoses; Pharmaceutical Preparations; Phase; Positioning Attribute; Reporting; Research; Research Contracts; Safety; Services; Signal Pathway; Structure; Surveys; System; Technology; Testing; Therapeutic Index; Thinking; Tissues; Toxic effect; Tumor Necrosis Factor-alpha; Universities; Variant; Wisconsin; Work; Xenograft procedure; analog; base; cancer cell; cancer therapy; cytotoxicity; cytotoxicity test; drug discovery; human TNF protein; human embryonic stem cell; in vitro Assay; indexing; inhibitor/antagonist; mouse model; novel; programs; receptor; sugar; trafficking; tumor

DESCRIPTION (provided by applicant): Epidemiological evidence points to the value of cardiac glycosides like digoxin and digitoxin for treatment of breast cancer and recent reports suggest they may be especially useful to treat non-small cell lung cancer. These and other findings underlie our belief that a cancer drug could be developed from such natural products. A major need in the development of a cancer drug lead will be to maximize the difference between inotropic activity, which could be cardiotoxic, and antitumor activity due to other effects of such glycosides. We will aim to discover a new drug for cancer treatment by optimizing the novel cardiac neoglycoside leads found in a cancer drug discovery program at the University of Wisconsin. The necessary IP to pursue this goal has been exclusively licensed to Centrose by the university. Two leads derived from digitoxigenin have already been found with nanomolar potency and high selectivity in cancer cell cytotoxicity tests, revealing an unexpected but potentially very useful influence of sugar structure on biological activity. They exhibit a >18-fold safer therapeutic index than digitoxin, based on their much weaker inhibition of the human Na/K-ATPase in a cell based assay. Synthesis of additional cardiac neoglycosides and comparison of their cytotoxicity towards cancer cell lines and inhibition of the Na/K-ATPase transporter in the cell based assay will therefore be the primary assays used to assess the potency and therapeutic index. The synthetic studies will involve surveying new cardenolide aglycones that carry a subset of the original library of hexoses and pentoses; and carrying out post-neoglycosylation chemistry at selected positions in the attached sugars using old and new leads. Secondary assays will involve (i) cell-based tests of potential cardiotoxicity due to long QT prolongations resulting from inhibition of hERG channel function or trafficking and to inhibition of repolarization of cardiomyocytes made from human embryonic stem cells, (ii) determination of effects on intracellular calcium ion transients in animal cardiomyocytes, because this is known to be correlated with cardiac arrhythmias in humans, and (iii) determinations of the effect of new analogs on induction of cancer cell apoptosis mediated through the Src/EGFR/ERK and TNF-alpha receptor/NFkB signalling pathways. Our goal will be to identify analogs with a better apparent therapeutic index than the current leads. The antitumor activity of two optimized leads chosen on the basis of the results of these studies will be determined by a contract research organization in xenograft mouse models of relevant human tumors. The research will aim to discover a new type of drug for cancer treatment that is based on chemical variations of the sugar components of cardiac glycosides that have been used for centuries to treat congestive heart failure. In the present study the goal will be to identify drug leads that have the greatest safety index between antitumor activity and potential cardiotoxicity.

描述（由申请人提供）：流行病学证据表明，强心苷如地高辛和洋地黄毒苷对治疗乳腺癌有价值，最近的报告表明，它们可能对治疗非小细胞肺癌特别有用。这些和其他发现支持了我们的信念，即癌症药物可以从这些天然产物中开发出来。开发癌症药物先导物的主要需要是最大化可能是心脏毒性的变力活性与由于此类糖苷的其他作用而产生的抗肿瘤活性之间的差异。我们的目标是通过优化威斯康星州大学癌症药物发现计划中发现的新型心脏新糖苷类先导化合物，发现一种治疗癌症的新药。追求这一目标所需的知识产权已由大学独家授权给Centrose。已经发现源自洋地黄毒苷的两种先导化合物在癌细胞毒性测试中具有纳摩尔效力和高选择性，揭示了糖结构对生物活性的意想不到但可能非常有用的影响。基于它们在基于细胞的测定中对人Na/K-ATP酶的弱得多的抑制，它们表现出比洋地黄毒苷安全>18倍的治疗指数。因此，在基于细胞的试验中，其他心脏新糖苷类的合成及其对癌细胞系的细胞毒性和Na/K-ATP酶转运蛋白的抑制的比较将是用于评估效价和治疗指数的主要试验。合成研究将涉及调查携带己糖和戊糖原始库的子集的新的腰果苷元;并使用旧的和新的先导物在所连接的糖中的选定位置进行新糖基化后化学。二次试验将涉及（i）基于细胞的潜在心脏毒性试验，该试验由hERG通道功能或运输的抑制以及由人胚胎干细胞制备的心肌细胞复极化的抑制引起的长QT间期延长引起，（ii）测定对动物心肌细胞中细胞内钙离子瞬变的影响，因为已知这与人类心律失常相关，和（iii）测定新类似物对通过Src/EGFR/ERK和TNF-α受体/NF κ B信号传导途径介导的癌细胞凋亡的诱导的作用。我们的目标将是确定具有比当前电极导线更好的表观治疗指数的类似物。根据这些研究结果选择的两种优化的先导化合物的抗肿瘤活性将由合同研究组织在相关人类肿瘤的异种移植小鼠模型中确定。该研究旨在发现一种新型的癌症治疗药物，该药物基于几个世纪以来用于治疗充血性心力衰竭的强心苷的糖组分的化学变化。在本研究中，目标是确定在抗肿瘤活性和潜在心脏毒性之间具有最大安全指数的药物先导化合物。