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

基本信息

批准号：
10342970
负责人：
Daniel Bachovchin
金额：
$ 64.12万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
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/10342970
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 Pharmacology Proline Proteins Recycling Research Research Project Grants Sampling Serine Serine Protease Serine Proteinase Inhibitors 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 improved in vivo inhibitor lead candidate leukemia mouse model multicatalytic endopeptidase complex novel therapeutic intervention novel therapeutics pre-clinical response small molecule small molecule inhibitor tool treatment strategy

项目摘要

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.

项目摘要急性髓样白血病（AML）是成人白血病的最常见形式。新的治疗策略是 AML迫切需要，因为总体五年生存率仍然不到25％。代理最近发现激活Card8炎症体是为了触发裂解细胞死亡的非炎症形式在包括AML癌细胞在内的造血细胞中，有可能成为新的抗AML药物。目前，唯一已知激活Card8炎症体的药物是小分子连续蛋白DPP8和DPP9的抑制剂（DPP8/9）。不幸的是，DPP8/9抑制剂也激活相关的NLRP1炎性体，与Card8炎症体不同，它触发了高度炎症形式其他细胞类型的细胞死亡，从而限制了DPP8/9抑制剂的治疗窗口 AML。该应用的中心假设是NLRP1和Card8之间的差异可以是开发选择性CARD8炎性体激活剂。申请人中产生的初步数据实验室并在本申请中进行了描述，表明酶PEPD的抑制剂有选择地激活 Card8炎症体并杀死AML癌细胞，而无需同时激活NLRP1炎症体。该应用的目的是开发PEPD抑制剂作为治疗的新治疗剂 AML。该项目由三个特定目的组成：1）优化有效和选择性的PEPD抑制剂； 2）到确定PEPD抑制剂在AML细胞中选择性激活CARD8的作用机理；和3）到探索AML小鼠模型中PEPD抑制剂的治疗潜力。这些成功完成目标将识别并表征第一批有选择地激活Card8炎症体的代理，并获得临床前概念证明了此类药物在治疗AML方面的效用。总体而言，这项工作具有很高的潜力不仅揭示了调节炎性体激活的基本机制，还可以利用针对癌症的治疗益处的炎性体激活。