DEVELOPMENT OF THERAPEUTIC CANDIDATES FOR TRIPLE NEGATIVE BREAST CANCER BASED ON MINOR GROOVE DNA BINDING AND HISTONE DEACETYLASE INHIBITION

• Grant number: 24/14854-6
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: January 01, 2025
• End date: December 31, 2025
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Organic Chemistry
• Principal Investigator: Flavio da Silva Emery
• Grantee: Lucas Melero Gavilha
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Triple negative breast cancer (TNBC) is the subtype with the worst prognosis and highest lethality among other types of breast cancer, as it is not responsive to the hormones progesterone and estrogen, and does not present human epidermal growth factor receptor-2 ( HER2). This subtype represents 15 to 20% of all breast cancer diagnoses, with a mortality rate of 40% in the five years following diagnosis. It contributes to approximately 25% of the total number of deaths related to this disease and does not have a specific targeted therapy. The present project seeks to develop molecules with dual inhibition capacity, based on a multitarget strategy with simultaneous action on the minor groove region of DNA and on the catalytic site of histone deacetylase (HDAC) enzymes, aiming to increase the quality and life expectancy of patients. from CMTN. The proposed work will be carried out based on the synthesis of carbamates, which will present fragments corresponding to the molecular profiles of HDAC inhibitors, as represented by Entinostat, a compound which is in the clinical trials phase, and minor groove ligands concomitantly. Some of the carbamates proposed in this work have already been synthesized with a structural profile corresponding to that of minor groove ligands and tested in cellular assays, proving to be more potent than cisplatin against CMTN cells, even without the insertion of groups that could interfere with the potency of these compounds by increased degree of complementarity in the catalytic sites of HDACs. From the synthesis of these new chemical entities, an unprecedented library of molecules will be obtained, which could be of great value for the subsequent development of anticancer compounds.