Prolidase Inhibitors as Therapeutic Agents for Acute Myeloid Leukemia

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.

Grant Number: 5R01CA266478-04
NIH Institute/Center: NIH
Principal Investigator: Daniel Bachovchin