Ponente
Descripción
Dipeptidyl peptidase IV (DPP4) and Neutral metallo-aminopeptidase (APN) are two abundant
ecto-aminopeptidases found in various human tissues [1]. DPP4 and/or APN can be
dysregulated during inflammatory pathologies, including cancer [2–4]. Being ectopeptidases,
they are key in the regulation of extracellular signals mediated by peptides, hence
thesimultaneous inhibition of both could be a useful therapeutic target in those tumors that
overregulate them [5–7]. The aim of this work was to obtain potent dual inhibitors of DPP4 and
APN, as well as to evaluate their effect on cellular viability in tumor lines that expressses one or
both enzymes. We identified three new non-peptide dual inhibitors of DPP4 and APN by virtual
screening and enzymatic assays. They are tight-binding competitive inhibitors of DPP4.
Molecular docking simulations supported the competitive behavior, and the selectivity of one of
the compounds in the DPP4 family. These molecules also inhibited APN, beeing non-competitive
inhibitors (α > 1) with Ki values in the µM range. Molecular docking simulations suggested the
novel inhibitors inhibit APN by an alternative mechanism to Zn2+ coordination. Using kinetic
assays, we determined that HL-60 tumor cells display both APN and DPP4 activities and that
MDA-MB-231 tumor cells express DPP4 activity. The inhibitors had a slight inhibitory effect on
human HEK-293 cell viability, but reduced the viability of APN+/DPP4+ and DPP4+ human tumor
cells more potently. The intraperitoneal injection of these compounds inhibited the DPP4 and
APN in rat brain, liver, and pancreas. In silico studies suggested inhibitors binding to serum
albumin contribute to blood-brain barrier crossing.
