Selective inhibitors of dipeptidyl peptidase 9 (DPP9) for induction of inflammatory cell death (pyroptosis) in cancer cells.

Dipeptidyl peptidase 9 (DPP9) is a cytosolic serine protease. The enzyme has lately attracted extensive international research attention, because of its recently discovered role in inflammatory cell death (pyroptosis). Among other things, it has been demonstrated that inhibition or knock-down of DPP9 leads to induction of pyroptosis in acute myeloid leukemia cells. Also in other oncology domains, DPP9 inhibition is currently investigated as a pyroptosis induction mechanism. In this form of programmed cell death, cancer cells are not only killed off, but they also release proteins that cause a strong, local upregulation of the innate immune system. This immunotherapeutic effect is generally seen as highly promising. To date, however, no clinically useful and selective DPP9 inhibitors have been reported. Very recently, however, the applicants discovered a series of low nanomolar small molecule DPP9 inhibitors with unprecedented selectivities toward all enzymes that are related to DPP9. Given the properties of these compounds and their significant valorisation potential, a patent application was submitted during June 2022. This IOF-POC project is expected to generate scientific data that should corroborate further the submitted patent application. In addition, these data should convince industrial partners to take a licence on the submitted patent. Next to new chemical data, this project application covers pharmacokinetic, pharmacodynamic and in vitro phenotypic research toward new inhibitors.

Keywords:DIPEPTIDYL PEPTIDASE

Disciplines:Medicinal and biomolecular chemistry not elsewhere classified, Molecular and cell biology not elsewhere classified