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Current Chemical Biology

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ISSN (Print): 2212-7968
ISSN (Online): 1872-3136

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Research Article

The Effect of Dipeptidyl Nitrile Derivatives on Pancreatic Ductal Adenocarcinoma Cells In Vitro

Author(s): Sabrina Mendes Botelho, Fernanda dos Reis Rocho, Lorenzo Cianni, Carlos A. Montanari and Andrei Leitão*

Volume 15, Issue 4, 2021

Published on: 28 December, 2021

Page: [278 - 286] Pages: 9

DOI: 10.2174/2212796815666211214111243

Price: $65

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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.

Keywords: Cell-based assays, SAR, cysteine protease inhibition, antineoplastic activity, colony formation assay, scratch healing assay, combination therapy.

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