Organogold compounds as “smart” residue specific chemical modifiers: towards new generation Gold-PROTACs (B03)

• Subject Area: Pharmacy ; Biological and Biomimetic Chemistry ; Hematology, Oncology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 514894665

To achieve novel pharmacophores and chemical probes relevant to the ubiquitin-proteasome system (UPS), the design of covalent amino acid (e.g. cysteine) modifiers is of paramount importance. We propose here a medicinal inorganic chemistry approach, using organogold compounds able to ‘catalyze’ bio-orthogonal C-S and C-Se bond-forming reactions under physiological conditions. An integrated investigational approach including chemoprotemoic/protemic, spectroscopic and computational methods, as well as in vitro pharmacological and imaging assays, will be used to elucidate the reactivity of the organogold compounds with target proteins relevant to the network, and their mechanisms of anticancer action focusing on NSCLC and MM. Moreover, the bioactive organogold moiety will enable its integration into a novel Gold-PROTAC construct enabling the selective degradation of specific UPS proteins and beyond.

• DFG Programme: CRC/Transregios
• Subproject of: TRR 387: Functionalizing the Ubiquitin System against Cancer - UbiQancer
• Applicant Institution: Technische Universität München (TUM)
• Project Head: Professorin Dr. Angela Casini