Prolidase Inhibitors as Therapeutic Agents for Acute Myeloid Leukemia

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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.