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

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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 ; Russowsky, Dennis ; Oliveira, Renato Jose Da Silva

• Document type: Journal article
• Source: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY REPORTS; v. 13, p. 16-pg., 2025-04-01.

Abstract

In this study, a series of novel hybrid compounds, 2-arylquinazolinechalcones, were synthesized and their antitumoral activities were evaluated. Among them, compounds 7b and 7n exhibited the highest cytotoxicity and selectivity rates for the triple-negative breast cancer cell line MDA-MB-231. In 3D spheroid culture, 7b and 7n decreased viability and increased cell death. Both compounds induced cell death primarily through the extrinsic pathway and promoted cell cycle arrest in G0/G1, possibly through increased expression of p27 and subsequent reduction in CDK2 levels. Additionally, they may trigger oxidative stress and DNA damage, as evidenced by elevated levels of H2AX activation, and compromise DNA repair pathways mediated by ATR and CHK1. To further explore the mechanism behind the observed cell cycle arrest, we performed phospho-RTK and phospho-MAPK Reverse Phase Protein Arrays to investigate changes in the expression of activated RTKs and MAPKs after treatment with 7b and 7n, compared to the negative control. These findings suggest that 7b and 7n are promising candidates for further development as targeted therapies for triple-negative breast cancer. (AU)

• FAPESP's process: 23/02032-9 - KRASgetaway: a preclinical investigation for control of the KRAS oncogene
• Grantee: Renato José da Silva Oliveira
• Support Opportunities: Regular Research Grants
• FAPESP's process: 22/05597-4 - Preclinical evaluation of antitumoral and toxicity activity of hybrid drugs (2-Arylquinazoline-chalcones) using a High Content Screening platform
• Grantee: Giulia Rodrigues Stringhetta
• Support Opportunities: Scholarships in Brazil - Master