Preclinical evaluation of antitumoral and toxicity activity of hybrid drugs (2-Arylquinazoline-chalcones) using a High Content Screening platform

• Grant number: 22/05597-4
• Support Opportunities: Scholarships in Brazil - Master
• Start date: April 01, 2023
• End date: September 30, 2024
• Field of knowledge: Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
• Principal Investigator: Renato José da Silva Oliveira
• Grantee: Giulia Rodrigues Stringhetta
• Host Institution: Hospital do Câncer de Barretos. Fundação Pio XII (FP). Barretos , SP, Brazil

Abstract

Antineoplastic drug development is based on the discovery of efficient molecules with lower cost and specific for the neoplastic cell target. In recent years, hybrid molecules' conceit has gained prominence, as they act synergistically, in reduced doses, and less likely to develop resistance, compared to the individual antineoplastic compounds. The screening of a new molecule can be performed by automated platforms, such as High Content Screening (HCS). This platform uses imaging parameters to determine cytotoxicity, which is then validated analytically and experimentally. The aim is to evaluate the antineoplastic potential of hybrid molecules using an HCS platform, and their ADME parameters in silico. According to our preliminary in silico results (CortellisTM), MDA-MB-231, T-47D and BT-474 breast cell lines will be used to screen for the 15 hybrid molecules. The hits will be obtained using a three-dimensional cell culture model (3D), monitored by fluorescence intensity (Calcein-AM), and subsequent statistical validation. Then, the cytotoxicity of the selected hits will be evaluated by real time (0-72 hours), using fluorescent assay RealTime-Glo" MT, and the evaluation of the parameters of death and cell cycle status will be measured by flow cytometry. Finally, the cells will be treated with the best hybrid molecules (IC50), to assess changes in proliferative signaling and death pathways, using protein arrays phopho-RTK, phopho-MAPK array and apoptosis signaling pathways arrays (R&D Systems).

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

STRINGHETTA, GIULIA RODRIGUES; MASS, EDUARDO BUSTOS; GOMES, IZABELA NATALIA FARIA; PEIXOTO, MARIA CLARA FONSECA; TEJADA, AMANDA HELENA; SUSUCCHI, LUCIANE; BEZERRA, ARYEL JOSE ALVES; RESENDE, PEDRO VICTOR SILVA; VENDRUSCULO, VINICIUS; REIS, MANUEL; et al. Design, synthesis and evaluation of quinazoline-chalcone hybrids as inducers of cell-cycle arrest and apoptosis in breast cancer via DNA damage and CDK2/ATR inhibition. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY REPORTS, v. 13, p. 16-pg., 2025-04-01. (23/02032-9, 22/05597-4)

RESENDE, PEDRO VICTOR SILVA; GOMESA, IZABELA NATALIA FARIA; PEIXOTO, MARIA CLARA; STRINGHETTA, GIULIA RODRIGUES; ARANTES, LIDIA MARIA REBOLHO BATISTA; KUZMIN, VLADIMIR ALEXANDROVICH; BORISSEVITCH, IOURI; REIS, RUI MANUEL; VAZQUEZA, VINICIUS DE LIMA; FERREIRA, LUCIMARA PERPETUA; et al. Evaluation of the antineoplastic properties of the photosensitizer biscyanine in 2D and 3D tumor cell models and artificial skin models. JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY, v. 262, p. 10-pg., 2024-12-12. (23/02032-9, 22/05597-4)