Scholarship 24/09739-3 - Descoberta de drogas, Química médica - BV FAPESP
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Zymographic analyses of cathepsin inhibitors using pancreatic (MIA PaCa-2) and liver (HepG2) cancer cell lines.

Grant number: 24/09739-3
Support Opportunities:Scholarships abroad - Research Internship - Doctorate (Direct)
Start date until: March 03, 2025
End date until: March 02, 2026
Field of knowledge:Physical Sciences and Mathematics - Chemistry
Principal Investigator:Andrei Leitão
Grantee:Sabrina Mendes Botelho
Supervisor: Manu Omar Platt
Host Institution: Instituto de Química de São Carlos (IQSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil
Institution abroad: National Institutes of Health, Bethesda (NIH), United States  
Associated to the scholarship:20/16799-1 - Study of expression, activity, and inhibition of cathepsins B, L, and S by dipeptidyl nitriles using pancreatic adenocarcinoma cell lines, BP.DD

Abstract

Cysteine cathepsin inhibitors present antineoplastic activity, as described in many reports in the literature. There is mounting evidence that these compounds could inhibit cancer progression and metastasis. Compounds Neq0709, Neq0712, Neq1031, and Neq1025 are inhibitors of cysteine cathepsins, being cytotoxic to the pancreatic (MIA PaCa-2) and liver (HepG2) cancer cells. However, the liver cancer cells do not express relevant amounts of cysteine cathepsins. Moreover, Neq0709 and Neq0712 have distinct profiles regarding the colony formation assay. Here, the mechanism of action for dipeptidyl nitrile derivatives from the Medicinal Chemistry Group will be studied using zymography for pancreatic and liver cancer cells to devise the distinct bioactivity based on the phenotypic and proteolytic inhibition results achieved so far. The fluorometric assay with the selective probe Z-FR-AMC gives the total amount of cysteine proteases' proteolytic activity. This result can be fine-tuned by differentially querying cathepsins B, K, L, S, and V with zymography to determine dipeptidyl nitriles and derivatives' inhibition and potency for each enzyme. mRNA knockout and knock-in experiments will be performed to identify the relevance of the chemicals in the cell lines. Therefore, the bioactivity profile for dipeptidyl nitriles and derivatives could be linked to the diverse phenotypic response previously described by the research group. This study will enable the identification of the bioactivity fingerprint for novel compounds, providing evidence to support the mechanism of action based on the cysteine cathepsin modulation.

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