Prolidase Inhibitors as Therapeutic Agents for Acute Myeloid Leukemia

脯氨酸酶抑制剂作为急性髓系白血病的治疗剂

• 批准号: 10573212
• 负责人: Daniel Bachovchin
• 金额: $ 62.83万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10573212
• 关键词: Active Sites; Acute Myelocytic Leukemia; Adult; Amino Acids; Binding; CASP1 gene; Cancer cell line; Cell Death; Cells; Chemicals; Communities; Data; Diagnosis; Dipeptidases; Dipeptides; Disease; Enzyme Inhibitor Drugs; Enzymes; Hematopoietic; Human; Immune system; Inflammasome; Inflammatory; Laboratories; Lead; Leukemic Cell; Lytic; Malignant Neoplasms; Molecular; Multiprotein Complexes; Mus; N-terminal; Normal Cell; Patients; Peptides; Pharmaceutical Preparations; Proliferating; Proline; Proteins; Recycling; Research; Research Project Grants; Sampling; Serine; Serine Protease; Serine Proteinase Inhibitors; Signal Induction; Signal Transduction; Specificity; Survival Rate; Testing; Therapeutic; Therapeutic Agents; Tissues; Toxic effect; United States; Work; Xaa-Pro dipeptidase; acute myeloid leukemia cell; analog; cancer cell; cell type; cytokine; cytokine release syndrome; design; efficacy evaluation; improved; in vivo; inhibitor; lead candidate; leukemia; mouse model; multicatalytic endopeptidase complex; novel therapeutic intervention; novel therapeutics; pharmacologic; pre-clinical; response; small molecule; small molecule inhibitor; tool

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.

项目摘要 急性髓性白血病（AML）是成人中最常见的白血病形式。新的治疗策略是 AML迫切需要，因为总体五年生存率仍低于25%。的试剂 最近发现激活CARD 8炎性体可触发非炎性形式的溶解性细胞死亡 在造血细胞，包括AML癌细胞中，因此有可能成为新的抗AML药物。 目前，已知激活CARD 8炎性体的唯一药理学试剂是小分子 丝氨酸蛋白酶DPP 8和DPP 9（DPP 8/9）的抑制剂。不幸的是，DPP 8/9抑制剂也会激活 相关的NLRP 1炎性体，与CARD 8炎性体不同，它触发了一种高度炎性的 其他细胞类型中的细胞死亡，从而限制了DPP 8/9抑制剂用于治疗 急性髓细胞白血病本申请的中心假设是NLRP 1和CARD 8之间的差异可以是 用于开发选择性CARD 8炎性小体激活剂。申请人提交的初步数据 实验室和本申请中所述方法显示，酶PEPD的抑制剂选择性地激活 CARD 8炎性体并杀死AML癌细胞，而不同时激活NLRP 1炎性体。 本申请的目的是开发PEPD抑制剂作为用于治疗以下疾病的新治疗剂： 急性髓细胞白血病该项目包括三个具体目标：1）优化有效和选择性PEPD抑制剂; 2） 确定PEPD抑制剂在AML细胞中选择性激活CARD 8的作用机制;和3） 探索PEPD抑制剂在AML小鼠模型中的治疗潜力。成功完成这些 目的是鉴定和表征选择性激活CARD 8炎性体的第一种试剂，并获得 这类药物在治疗AML中的效用的临床前概念验证。总体而言，这项工作具有很高的潜力 不仅揭示了调节炎性小体激活的基本机制， 炎性体活化用于对抗癌症的治疗益处。