Selective Inhibitors of Fibroblast Activation Protein (FAP) with a (4-Quinolinoyl)-glycyl-2-cyanopyrrolidine Scaffold

Abstract

Fibroblast activation protein (FAP) is a serine protease that is generally accepted to play an important role in tumor growth and other diseases involving tissue remodeling. Currently there are no FAP inhibitors with reported selectivity toward both the closely related dipeptidyl peptidases (DPPs) and prolyl oligopeptidase (PREP). We present the discovery of a new class of FAP inhibitors with a N-(4-quinolinoyl)-Gly-(2-cyanopyrrolidine) scaffold. We have explored the effects of substituting the quinoline ring and varying the position of its sp 2 hybridized nitrogen atom. The most promising inhibitors combined low nanomolar FAP inhibition and high selectivity indices (>10 3 ) with respect to both the DPPs and PREP. Preliminary experiments on a representative inhibitor demonstrate that plasma stability, kinetic solubility, and log D of this class of compounds can be expected to be satisfactory.

Crystal structure of Porphyromonas gingivalis dipeptidyl peptidase 4 and structure-activity relationships based on inhibitor profiling

“…Gly-Pro-p-nitroanilide was purchased from Sigma (Diegem, Belgium). Inhibitor synthesis was described in the original publications [20][21][22][23][24][25][26][27][28][29][30][31][32][33]. Synthetic peptides were acquired from Thermo Scientific.…”

“…For the latter compounds IC50 values ranged between 10 and 0.05 µM (supplementary material, Table S2). Compounds with a protected amino terminus, targetting PREP and FAP [22,23,25,30], showed no inhibition, confirming that pgDPP4 is a true dipeptidyl peptidase.…”

“…The collection used in the present work includes compounds that have been developed and characterized at the University of Antwerp during a longstanding research program on various peptidases, including DPP4, DPP2, DPP8, DPP9, fibroblast activating protein-α (FAP) and prolyl oligopeptidase (PREP). They are based on several chemical scaffolds [20][21][22][23][24][25][26][27][28][29][30][31][32][33]. The collection also includes reference compounds, such as the antidiabetic drugs 6 sitagliptin, vildagliptin and linagliptin, and prototypical DPP2, DPP8/9 and FAP inhibitors.…”

Selective inhibitors of fibroblast activation protein (FAP) with a xanthine scaffold

“…The latter is a determining part of an S3-binding pharmacophore for FAP that we described earlier. 18 None of the modications present in 13h-13j, led to further optimised FAP inhibitors. In the absence of direct structural clues for further optimization of the R 1 group, further expansion of this series was not planned at this point.…”

Effects of B2O3 (boron trioxide) on colon cancer cells: our first-step experience and in vitro results

“…In 2004, a phase II clinical trial of PT-100 was initiated in the treatment of advanced non-small-cell lung cancer (Cunningham, 2007). The compound, which was put on hold in 2007 due to efficacy problems, has recently been considered as a therapeutic drug for many metastatic cancers such as kidney cancer, pancreatic adenocarcinoma, non-small-cell lung cancer, and chronic lymphocytic leukemia, and phase II clinical studies are being carried out (Jansen et al, 2013). Talabostat) induced strong antitumor immune responses in similar cancer models (Okondo et al, 2018).…”