Introduction:

Cancer is the second leading cause of death in our country and in the world. Within the attractive targets for the design of new anticarcinogenic agents we find aminopeptidases. In particular, within the M1 family, the neutral aminopeptidase (APN, EC 3.4.11.2), the acid aminopeptidase (APA, EC 3.4.11.7) and within the S9 family of serine peptidases, the enzyme dipeptidyl peptidase IV (DPP-IV, EC 3.4.14.5); the before mentioned are targets established for the development of new anticancer agents due to their over-expression in different types of cancer. Considering the biomedical relevance of the inhibition of APN, APA and DPP-IV, the main goal of this paper is to identify new inhibitors of these enzymes with potential biomedical applications.

Methods:

They were addressed two strategies for the identification of new inhibitors of the enzymes under study: a) identification and biochemical characterization of new low molecular mass inhibitors of APN, APA and DPP-IV, for which virtual screenings were carried out in the base of low molecular mass compounds HitFinder, Maybridge (ThermoFisher), and b) biochemical characterization of the inhibition of APN, APA and DPP-IV by bestatin and bacitracin as new inhibitors of these enzymes. Subsequently, it was carried out the kinetic validation of the new identified inhibitors, they were carried out in silico structure: function relationship studies, it was also evaluated the biodistribution in a rat model as well as their cytotoxic effects on APN+/DPP-IV+ tumor lines.

Results:

They were identified and kinetically validated five new dual inhibitors of APN, APA and DPP-IV with non-competitive inhibition mechanisms in most cases. In silico studies of Enzyme: inhibitor complexes allowed the identification of non-conserved residues within the corresponding family and this lays the foundations for the rational design of highly selective APN, APA and DPP-IV inhibitors with greater biomedical potential. They were identified for the first time, using a methodology established in this work the presence of APN and DPP-IV in cancer tumor lines with high incidence and mortality in Cuba and the world. The new inhibitors have promising effects on these APN+/DPP-IV+ tumor lines. Conclusions: They are reported for the first-time new inhibitors of APN, APA and DPP-IV, with different inhibition mechanisms, some of them non-competitive, which are more advantageous from the therapeutic point of view than competitive inhibitors, with promising effects on tumor lines related to cancers with high incidence and mortality in Cuba.

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