Prolidase Inhibitors as Therapeutic Agents for Acute Myeloid Leukemia

项目总结 急性髓系白血病(AML)是成人最常见的白血病类型。新的治疗策略是 急性髓系白血病迫切需要，因为总体五年存活率仍然不到25%。符合条件的代理 最近发现，激活CARD8炎性小体可以触发一种非炎症性的溶细胞死亡 在包括AML癌细胞在内的造血细胞中，具有成为抗AML新药的潜力。 目前，已知的唯一能激活CARD8炎症体的药物是小分子 丝氨酸蛋白酶抑制剂DPP8和DPP9(DPP8/9)。不幸的是，DPP8/9抑制剂也激活了 相关的NLRP1炎症小体，与CARD8炎症小体不同，它触发一种高度炎症形式的 其他细胞类型的细胞死亡，从而限制了DPP8/9抑制剂治疗白血病的治疗窗口 AML。这个应用程序的中心假设是NLRP1和CARD8之间的差异可以是 开发用于开发选择性CARD8炎症体激活剂。申请人提交的初步数据 实验室和在本申请中描述的结果表明，PEPD酶的抑制剂选择性地激活 CARD8炎症体并杀死AML癌细胞，而不同时激活NLRP1炎症体。 本应用的目的是开发PEPD抑制剂作为治疗糖尿病的新的治疗药物。 AML。该项目包括三个具体目标：1)优化有效和选择性的PEPD抑制剂；2) 确定PEPD抑制剂在AML细胞中选择性激活CARD8的作用机制；以及3) 探索PEPD抑制剂在急性髓细胞白血病小鼠模型中的治疗潜力。成功完成这些任务 AIMS将鉴定和表征第一批选择性激活CARD8炎症体的药物，并获得 此类药物在治疗急性髓细胞白血病中的效用的临床前概念证明。总体而言，这项工作潜力很大 不仅要揭示调节炎性小体激活的基本机制，而且要利用 激活炎性小体，对癌症有治疗作用。

PROJECT SUMMARY Acute myeloid leukemia (AML) is the most common form of leukemia in adults. New therapeutic strategies are urgently needed for AML, as the overall five-year survival rate remains at less than 25 percent. Agents that activate the CARD8 inflammasome were recently discovered to trigger a non-inflammatory form of lytic cell death in hematopoietic cells, including AML cancer cells, and thus have potential to become new anti-AML drugs. Currently, the only pharmacological agents known to activate the CARD8 inflammasome are small molecule inhibitors of serine proteases DPP8 and DPP9 (DPP8/9). Unfortunately, DPP8/9 inhibitors also activate the related NLRP1 inflammasome, which, unlike the CARD8 inflammasome, triggers a highly inflammatory form of cell death in other cell types and thereby limits the therapeutic window of DPP8/9 inhibitors for the treatment of AML. The central hypothesis of this application is that the differences between NLRP1 and CARD8 can be exploited to develop selective CARD8 inflammasome activators. The preliminary data produced in the applicant’s laboratory and described in this application show that inhibitors of the enzyme PEPD selectively activate the CARD8 inflammasome and kill AML cancer cells without simultaneously activating the NLRP1 inflammasome. The objective of this application is to develop PEPD inhibitors as new therapeutic agents for the treatment of AML. This project consists of three specific aims: 1) to optimize potent and selective PEPD inhibitors; 2) to determine the mechanism of action of PEPD inhibitors for selective activation of CARD8 in AML cells; and 3) to explore the therapeutic potential of PEPD inhibitors in mouse models of AML. Successful completion of these aims will identify and characterize the first agents that selectively activate the CARD8 inflammasome, and obtain preclinical proof of concept for the utility of such agents in treating AML. Overall, this work has high potential to not only reveal fundamental mechanisms that regulate inflammasome activation, but also to harness inflammasome activation for therapeutic benefit against cancer.