In vitro pharmacological study of dipeptidyl nitrile derivatives against liver and pancreatic cancer cells.

• Grant number: 24/01035-7
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: May 01, 2024
• End date: November 10, 2025
• Field of knowledge: Physical Sciences and Mathematics - Chemistry
• Principal Investigator: Andrei Leitão
• Grantee: Vinicius Gonçalves Satkauskas
• Host Institution: Instituto de Química de São Carlos (IQSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil

Abstract

Pancreatic and liver cancers, characterized by elevated mortality rates, pose significant challenges in chemotherapy, leading to the exploration of novel therapeutic approaches. Cathepsins B, L, and S have been identified as key players in the neoplastic process, offering potential targets for covalent reversible and irreversible inhibitors using dipeptidyl nitrile derivatives. Dipeptidyl nitrile derivatives and their oxidized forms (oximes) have shown promise in various cancer types. In this study, we will perform in vitro investigations utilizing two-dimensional cell cultures with pancreatic carcinoma cell lines (MIA PaCa-2 and BxPC-3) and a liver cell line (HepG2). Our research focuses on quantifying the potency of a series comprising 15 compounds against the cancer cell lines to link the cell morphology to the pharmacological activity and cysteine cathepsin inhibition. We will employ analytical methods, including colorimetry, fluorimetry, fluorescence microscopy, and electron microscopy, to assess the cellular phenotypic response. We aim to establish a correlation between enzymatic inhibition, pharmacological activity, and the cellular phenotypic response. The assays will be conducted with both isolated inhibitors and in combination with a reference drug. This project aims to contribute to the identification of new compounds with therapeutic potential, thereby facilitating the development of a promising therapeutic strategy in a drug discovery effort. Our findings will offer insights into the potential of dipeptidyl nitrile derivatives as effective agents for pancreatic and liver carcinoma treatments.