Acute myeloid leukemia (AML) is an aggressive malignancy of the blood and bone marrow, characterized by the rapid proliferation of abnormal myeloid cells. It is the most common type of acute leukemia in adults and remains challenging to treat due to its high relapse rate and resistance to conventional therapies. Despite advances in chemotherapy, targeted therapies, and hematopoietic stem cell transplantation, long-term remission remains elusive for many patients. Therefore, identifying novel therapeutic targets and innovative treatment strategies is crucial for improving clinical outcomes in AML.
Dipeptidyl-peptidase 9 (DPP9) is a proline-selective serine protease belonging to the peptidase S9 family. While initially recognized for its role in protein turnover and immune regulation, recent studies have highlighted its significance in AML. Notably, the inhibition of DPP9 has been shown to induce inflammatory cell death (pyroptosis) selectively in myeloid leukemia cells, positioning it as an attractive target for therapeutic intervention. Mechanistically, DPP9 regulates the activation of NLRP1, a key inflammasome sensor involved in pyroptosis. Inhibition of DPP9 disrupts its interaction with NLRP1, leading to inflammasome activation, caspase-1 activation, and subsequent cell death via pyroptosis. This targeted mechanism offers a promising approach for eradicating AML cells while sparing healthy tissues. However, to date, only small-molecule inhibitors of DPP9 have been reported, and their effects on the DPP9-NLRP1 interaction remain limited, showing only mild destabilization of the protein-protein interaction (PPI).
Targeted Protein Degradation (TPD) is an emerging and highly promising therapeutic modality in drug discovery, offering an alternative to traditional small-molecule inhibition. The first and most well-established TPD approach is PROTAC (PROteolysis Targeting Chimera) technology, which exploits the ubiquitin-proteasome system (UPS) to selectively degrade proteins of interest (POI).
Unlike conventional small-molecule inhibitors that require sustained occupancy to exert their effects, PROTACs function catalytically by inducing molecular proximity between the POI (in this case, DPP9) and an E3 ubiquitin ligase. This leads to the ubiquitination and subsequent proteasomal degradation of DPP9, effectively eliminating its cellular function. This catalytic mode of action allows PROTACs to achieve prolonged pharmacodynamic effects with lower dosages, reducing the likelihood of off-target toxicity and drug resistance.
Beyond PROTACs, other TPD strategies, such as AUTACs (Autophagy-Targeting Chimeras), offer additional avenues for targeted protein clearance through the autophagy-lysosome pathway. These approaches provide alternative mechanisms for degrading disease-associated proteins, broadening the potential for TPD-based therapies in AML.
The primary goal of this project was to design, synthesize, and validate small-molecule degraders targeting DPP9 for AML treatment. Successful implementation of this approach could revolutionize AML therapy by providing a highly selective, durable, and well-tolerated treatment option. By harnessing the power of targeted protein degradation, this strategy holds the potential to improve patient outcomes, reduce relapse rates, and pave the way for next-generation cancer therapeutics.
