Optimization of HDAC6 and JAK3 Hybrid Inhibitors Based on deazapurine-benzo-ydroxamates for the Treatment of Hematological Cancers

• Grant number: 24/22137-2
• Support Opportunities: Scholarships in Brazil - Master
• Start date: May 01, 2025
• End date: February 28, 2027
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Roberto Parise Filho
• Grantee: Sara Dias da Silva
• Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Hematological cancers, such as leukemias and lymphomas, exhibit a high rate of resistance to conventional treatments, demanding new therapeutic approaches. This project proposes the development of hybrid inhibitors that simultaneously target HDAC6 and JAK3, proteins associated with tumor proliferation and therapy resistance. The originality of the proposal lies in the use of bioisosterism by replacing the purine nucleus with a deazapurine nucleus, which enhances the electronic and metabolic properties of the compounds while increasing interactions with the molecular targets. Based on the scaffold of the previously synthesized compound 4d, structural modifications will also be undertaken to improve selectivity and efficacy. The compounds will be evaluated for cytotoxicity, mechanisms of cell death, as well as enzymatic affinity and selectivity, aiming to identify promising candidates with high potency and low toxicity in non-tumor cells. The research seeks to create innovative therapies for hematological malignancies, contributing to scientific advancements and potential clinical applications.