Title:The Effect of Dipeptidyl Nitrile Derivatives on Pancreatic Ductal Adenocarcinoma
Cells In Vitro
Volume: 15
Issue: 4
Author(s): Sabrina Mendes Botelho, Fernanda dos Reis Rocho, Lorenzo Cianni, Carlos A. Montanari and Andrei Leitão*
Affiliation:
- Medicinal & Biological Chemistry Group (NEQUIMED), São Carlos Institute of Chemistry (IQSC), University of São Paulo (USP) – Av. Trabalhador São-carlense, 400, São Carlos, SP,Brazil
Keywords:
Cell-based assays, SAR, cysteine protease inhibition, antineoplastic activity, colony formation assay, scratch healing assay, combination therapy.
Abstract: Aims: This study aims to evaluate the bioactivity of dipeptidyl nitrile inhibitors of human
cysteine cathepsins that could work as anticancer agents in a drug discovery and development
project.
Background: Human lysosomal cysteine proteases promote cancer progression, migration, and metastasis,
targeted by inhibitors.
Objective: Here, 19 cysteine protease inhibitors known as dipeptidyl nitriles were tested using MIA
PaCa-2 pancreatic cancer cells and Balb/3T3 clone A31 non-tumoral mouse fibroblasts.
Methods: In vitro assays evaluated cell migration, colony formation, inhibition of the enzymatic activity
in cell lysates, and combination therapy with gemcitabine.
Results: There were mixed results; the inhibitors reduced the number of colonies but did not affect
the total area. Cells migrated despite enzyme inhibition by Neq0709 and Neq0712. As expected,
the compounds were non-cytotoxic; they improved the potency of gemcitabine in the combined
therapy assay, especially for Neq0707.
Conclusion: In summary, our findings revealed the complexity of dealing with the translation from
biochemical to cell-based assays in the hit-to-lead step.
