Evaluation of Novel Sansalvamide A Derivatives as Potential Anti-Cancer Agents

新型 Sansalvamide A 衍生物作为潜在抗癌药物的评价

• 批准号: 7620540
• 负责人: ANA M NAVARRO
• 金额: $ 17.71万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7620540
• 关键词: Antineoplastic Agents; Binding; C-terminal; Class; Development; Evaluation; Goals; Lead; Malignant Neoplasms; Malignant neoplasm of pancreas; Marketing; N-terminal; Pancreas; Pharmaceutical Preparations; Site; Structure; Therapeutic; Toxic effect; Xenograft Model; abstracting; analog; base; cellular targeting; chemotherapeutic agent; colon cancer cell line; cytotoxic; inhibitor/antagonist; inositol hexakisphosphate kinase; interest; killings; neoplastic cell; novel; pancreas xenograft; scaffold

ABSTRACT The sansalvamide A (San A) scaffold is a promising structure for the development of novel cancer therapeutics. We have used the San A scaffold to produce 7 compounds that are cytotoxic to pancreatic and colon cancer cell lines at nanomolar concentrations. The San A derivatives are of particular interest because they do not share structural homology with other classes of marketed cancer therapeutics, they appear to inhibit an established target (Hsp90) at a novel site, and they are significantly more potent than the drugs currently available for the treatment of colon and pancreatic cancer. Known Hsp90 inhibitors interact with the N-terminal domain whereas our compounds are unique in that they target the C-terminal domain and block the binding of inositol hexakisphosphate kinase 2 (IP6K2). It is the overall goal of this project to develop a novel chemotherapeutic agent based on the San A scaffold. It is our hypothesis that analogs of San A with even greater potency and selectively can be synthesized by modifying key structural features identified in our preliminary studies. The specific aims are to: a) Conduct structure-activity studies of San A derivatives and select a lead candidate compound, b) Identify the key cellular targets and determine the mechanism by which San A analogs kill tumor cells, and c) Determine the efficacy and toxicity of a lead San A derivative in colon and pancreatic xenograft models.

抽象的 Sansalvamide A (San A) 支架是一种有前途的新型癌症发展结构 疗法。我们使用 San A 支架生产了 7 种对胰腺和胰腺具有细胞毒性的化合物。 纳摩尔浓度的结肠癌细胞系。 San A 衍生品特别令人感兴趣，因为 它们与其他类别的市售癌症疗法不具有结构同源性，但它们似乎 在新位点抑制既定靶点 (Hsp90)，并且它们比药物更有效 目前可用于治疗结肠癌和胰腺癌。已知的 Hsp90 抑制剂与 N 端结构域，而我们的化合物的独特之处在于它们靶向 C 端结构域并阻断 肌醇六磷酸激酶 2 (IP6K2) 的结合。该项目的总体目标是开发一种新颖的 基于San A支架的化疗剂。我们的假设是 San A 的类似物甚至 通过修改我们确定的关键结构特征可以合成更大的效力和选择性 初步研究。具体目标是： a) 进行 San A 衍生物的结构-活性研究和 选择主要候选化合物，b) 识别关键细胞靶点并确定其作用机制 San A 类似物杀死肿瘤细胞，并且 c) 确定先导 San A 衍生物在结肠中的功效和毒性 和胰腺异种移植模型。