Scaffold of N-(2-(2-(tosylcarbamoyl)hydrazinyl)ethyl)isonicotinamidereveals anticancer effects through selective inhibition of FAP

The limited expression of fibroblast activation protein (FAP) makes it an alluring target for cancer therapy in the activated epithelial stroma and is related to more than 90% of epithelial cancer. Among the three-enzymatic activities of FAP, the dipeptidyl peptidase activity particularly contributes to tumor progression. Repurposing of small-molecule inhibitors can be a potential therapeutic strategy in both the prevention and treatment of cancer. Drug repurposing was used for this study and doxorubicin was considered a reference drug. Due to similar domain structure and high homologous structure of FAP and dipeptidyl peptidase-4 (DPP IV), the inhibitors of DPP IV were chosen for the study. Previous studies revealed that some drugs of the gliptin and sulfonylureas families are potential DPP IV inhibitors and hence, could be enzymatic inhibitors of FAP. The aim of this study was to predict a new therapeutic indication of the drug(s) from the gliptin family that will regulate fibroblast activation protein (FAP), responsible for tumor growth. An in silico study was carried out with some anti-diabetic drugs. They binding affinities after structural modifications showed significant improvements. Binding affinity values of the substituted structures of some antidiabetic drugs were found using PyRx and interactions were observed using Discovery Studio. The ADMET properties of the compounds were also studied. The most promising drug found from this study, tolbutamide showed a binding affinity of 9.4 kcal/mol and exhibited the following ADMET properties: it did not cross the blood brain barrier and had impressive human intestinal absorption. It was observed to be a non-inhibitor of p glycoprotein inhibitor. Furthermore, the results of AMES toxicity demonstrated the substituted compound was non-AMES toxic. It also interacted with important key residues lining the binding pockets. Overall, the drug seemed to be a selective inhibitor of Fibroblast Activation Protein. It could possibly suppress dipeptidyl peptidase activity of FAP and may play a pragmatic role in epithelial cancer.