Organometallic Compounds for Anticancer Applications: PROTACs targeting

• Grant number: 24/04343-4
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Start date: August 01, 2024
• End date: July 31, 2025
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Inorganic Chemistry
• Principal Investigator: Camilla Abbehausen
• Grantee: Josielle Vieira Fontes
• Supervisor: Angela Casini
• Host Institution: Instituto de Química (IQ). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Institution abroad: Technical University of Munich (TUM), Germany
• Associated to the scholarship: 22/06410-5 - Metal complexes as specific enzymatic inhibitors for the treatment of Leishmaniasis: cysteine-proteases and trypanothione reductase, BP.DR

Abstract

Metal-based drugs, particularly organometallic compounds featuring N-heterocyclic carbenes (NHCs), are crucial in medicinal chemistry for combating diseases. Recent research highlights the significant potential of symmetric arylated NHC gold(I) and copper(I) complexes, with ongoing investigations into their mechanisms involving reactive oxygen species (ROS) and reactive nitrogen species (RNS) activation. Research at the Technical University of Munich aims to explore the bioactivity of these organometallic compounds against human cancer cells. Pharmacological testing will involve Au(I)/Cu(I) complexes integrated into proteolysis targeting chimera (PROTAC) compounds, targeting the seleno-enzyme thioredoxin reductase (TrxR). Utilizing biophysical, cellular, and computational methods, this study seeks to evaluate enzyme inhibition and TrxR degradation via the ubiquitin pathway. Initial findings hint at the potential for other organogold compounds to serve as PROTAC degraders. Future investigations will delve into uptake mechanisms, ROS production, and mitochondrial damage, refining metallodrugs for enhanced therapeutic efficacy across diseases, including cancer and neglected tropical diseases.