Targeting Calpain for Novel Anticancer Agents

靶向钙蛋白酶的新型抗癌药物

• 批准号: 6718554
• 负责人: Isaac O. Donkor
• 金额: $ 13.05万
• 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 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6718554
• 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）：CALPAINS是由第二信使Ca 2调节的一类细胞内半胱氨酸蛋白酶。据报道，几种Calpain同工型I和II calpains I和II是哺乳动物细胞中最普遍的。据认为，CALPAIN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，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，多种信号酶（例如蛋白激酶C，PP60 SRC）和粘附分子整合素和e-Cadherin已与人类的质谱相互依赖。在细胞培养研究中也证明了这一点，抑制钙蛋白酶会触发癌细胞系的凋亡。这些研究表明，钙蛋白酶是发现新的抗肿瘤剂的潜在新癌症靶标。然而，缺乏体内研究（动物研究），这些研究验证了钙蛋白酶作为抗癌药物发现的可行癌症靶标。体外CALPAIN抑制与体内抗癌活性之间的联系不足，部分原因是大多数钙蛋白酶抑制剂的代谢不稳定。这构成了一个很大的差距，以便验证钙蛋白酶为新的癌症靶标。该提案的直接目的是通过开发一系列有效，选择性和代谢稳定的独特的钙蛋白酶抑制剂来填补这一空白，以用作验证Calpain作为新的癌症靶标的工具。长期目标是将钙蛋白酶抑制剂作为一种新的抗癌剂。具体目的是：（1）使用基于结构的分子设计方法来设计和合成代谢稳定的钙蛋白酶抑制剂； （2）确定化合物对钙蛋白酶抑制与其他蛋白酶的效力和选择性； （3）确定化合物的代谢稳定性； （4）确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谱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标。此外，由于其代谢稳定性，这些化合物是用于研究钙蛋白酶内作用的有用生物医学工具。这些化合物也是潜在的抗癌剂。