Discovery of highly selective inhibitors and activity-based probes for dipeptidyl peptidase 9 (DPP9).

Dipeptidyl peptidase 9 (DPP9) is a cytosolic serine protease. It is related to, among others, the diabetes drug target DPP4 and to DPP8. Especially DPP8 is highly homologous with DPP9 and both enzymes generally occur simultaneously in the cells. Recent research shows that DPP9 is an NLRP1-inflammasome inhibitor and, most notably, that DPP9 inhibition leads to inflammatory cell death (pyroptosis) in most Acute Myeloid Leukemia (AML) cell lines. This effect is also reproduced in mouse models of AML, indicating that DPP9-inhibition could be an innovative strategy to treat AML and related hematological malignancies. To date, only non-selective DPP8/9-inhibitors have been reported and these compounds are known to have toxicity and stability issues, limiting their application to preclinical settings. Recent, preliminary data obtained by the hosting labs show that specific structural modifications of the marketed DPP4 inhibitor vildagliptin, yields molecules with unprecedented selectivity for DPP9 over all related proteases. These molecules will be further optimized in this project to obtain analogues with maximized DPP9 selectivity. All molecules will be evaluated for DPP9 potency/selectivity. Selected representatives will be further investigated in cells and for the most promising molecule, in vivo pharmacokinetics will be determined in healthy mice. Finally, the most promising inhibitor will also be used as a structural template for activity-based biomarker probes of DPP9.

Keywords:INHIBITOR DESIGN

Disciplines:Organic chemical synthesis, Organic chemistry not elsewhere classified, In vitro testing, Drug discovery and development not elsewhere classified, Medicinal chemistry