Targeting Calpain for Novel Anticancer Agents

靶向钙蛋白酶的新型抗癌药物

• 批准号: 6889227
• 负责人: Isaac O. Donkor
• 金额: $ 11.9万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6889227
• 关键词: antineoplastics; athymic mouse; calpain; cell line; cytotoxicity; drug design /synthesis /production; drug metabolism; drug screening /evaluation; human genetic material tag; laboratory rat; pharmacokinetics; protease inhibitor

DESCRIPTION (provided by applicant): Calpains are a class of intracellular cysteine proteases regulated by the second messenger, Ca 2. Several Calpain isoforms have been reported of which Calpains I and II are the most ubiquitous in mammalian cells. Calpains are believed to be important modulators of a number of physiologic and pathologic events in cells. The enzyme has a broad substrate specificity and many Calpain substrates such as the transcription factors c-Fos and c-Jun, the tumor suppressor protein p53, multiple signaling enzymes (e.g., protein kinase C, pp60 src) and the adhesion molecules integrin and E-cadherin have been implicated in the pathogenesis of different human tumors. It has also been demonstrated in cell culture studies that inhibition of Calpain triggers apoptosis in cancer cell lines. These studies suggest that Calpain is a potential new cancer target for the discovery of a new class of antitumor agents. There is however, a paucity of in vivo studies (animal studies) that validate Calpain as a viable cancer target for anticancer drug discovery. The link between in vitro Calpain inhibition and in vivo anticancer activity is under-explored due in part to the metabolic instability of most Calpain inhibitors. This constitutes a significant gap that must be addressed in order to validate Calpain as a new cancer target. The immediate goal of this proposal is to fill this gap by developing a unique series of Calpain inhibitors that are potent, selective, and metabolically stable for use as tools to validate Calpain as a new cancer target. The long-term goal is to develop Calpain inhibitors as a new class of anticancer agents. The specific aims are to: (1) use structure-based molecular design approaches to design and synthesize metabolically stable Calpain inhibitors; (2) determine the potency and selectivity of the compounds towards Calpain inhibition versus other proteases; (3) determine the metabolic stability of the compounds; (4) determine the in vitro cytotoxicity and in vivo efficacy of the compounds; (5) determine if the inhibitory potency (Ki) of the inhibitors correlate with their in vitro cytotoxicity profiles as well as in vivo antitumor efficacy; (6) determine the mechanism(s) of Calpain inhibitor-induced cytotoxicity. The results of the proposed studies will validate Calpain as a new cancer target for anti-tumor drug discovery. Additionally, the compounds are useful biomedical tools for investigating the intracellular roles of Calpain due to their metabolic stability. The compounds are also potential anticancer agents.

描述（由申请人提供）：钙蛋白酶是一类由第二信使Ca 2 调节的细胞内半胱氨酸蛋白酶。已报道了几种钙蛋白酶亚型，其中钙蛋白酶I和II在哺乳动物细胞中最普遍。钙蛋白酶被认为是细胞中许多生理和病理事件的重要调节剂。该酶具有广泛的底物特异性和许多钙蛋白酶底物，例如转录因子 c-Fos 和 c-Jun、肿瘤抑制蛋白 p53、多种信号传导酶（例如蛋白激酶 C、pp60 src）以及粘附分子整合素和 E -钙粘蛋白与不同人类肿瘤的发病机制有关。细胞培养研究还证明，抑制钙蛋白酶会引发癌细胞系凋亡。这些研究表明钙蛋白酶是发现一类新型抗肿瘤药物的潜在新癌症靶点。然而，缺乏体内研究（动物研究）来验证钙蛋白酶作为抗癌药物发现的可行癌症靶点。体外钙蛋白酶抑制与体内抗癌活性之间的联系尚未得到充分探索，部分原因是大多数钙蛋白酶抑制剂的代谢不稳定。为了验证 Calpain 作为新的癌症靶点，必须解决这一重大差距。该提案的直接目标是通过开发一系列独特的钙蛋白酶抑制剂来填补这一空白，这些抑制剂具有强效、选择性和代谢稳定性，可用作验证钙蛋白酶作为新癌症靶点的工具。长期目标是将钙蛋白酶抑制剂开发为一类新型抗癌药物。具体目标是：（1）利用基于结构的分子设计方法设计和合成代谢稳定的钙蛋白酶抑制剂； (2) 确定化合物与其他蛋白酶相比对钙蛋白酶抑制的效力和选择性； (3)测定化合物的代谢稳定性； (4)测定化合物的体外细胞毒性和体内功效； (5) 确定抑制剂的抑制效力（Ki）是否与其体外细胞毒性特征以及体内抗肿瘤功效相关； (6)确定钙蛋白酶抑制剂诱导的细胞毒性的机制。拟议研究的结果将验证钙蛋白酶作为抗肿瘤药物发现的新癌症靶点。此外，由于其代谢稳定性，这些化合物是研究钙蛋白酶细胞内作用的有用的生物医学工具。这些化合物也是潜在的抗癌剂。

项目成果

Apoptosis induced by novel aldehyde calpain inhibitors in human tumor cell lines.

• DOI: 10.3892/ijo.29.3.655
• 发表时间: 2006-09
• 期刊: International journal of oncology
• 影响因子: 5.2
• 作者: Na Guan;Rajani Korukonda;E. Hurh;Thomas D. Schmittgen;I. Donkor;J. Dalton

A novel series of urea-based peptidomimetic calpain inhibitors.

一系列新型的基于尿素的拟肽钙蛋白酶抑制剂。

• DOI: 10.1016/j.bmcl.2005.12.068
• 发表时间: 2006
• 期刊: Bioorganic & medicinal chemistry letters.
• 作者: Sanders,MLee;Donkor,IsaacO
• 通讯作者: Donkor,IsaacO