Design and synthesis of Hsp90 PROTAC degraders as potential anticancer agents

Abstract

Hsp90 (Heat Shock Protein 90) is a chaperon protein which plays role in protein folding and maintaining protein structures. It is overexpressed in cancer and stabilizes many oncoproteins and as such represents a good target for developing anticancer drugs. The majority of approved drugs today operate by occupancy-driven pharmacology. The PROTAC approach as a strategy in creating novel drugs utilizes event-driven pharmacology in which target proteins are degraded. In recent years it emerged as very attractive and conceptually novel approach in drug discovery and development. PROTACs are molecules with two warheads connected with a linker with general structure: Ligand(protein of interest)-Linker-Ligand(E3 ligase). One warhead binds the protein of interest (POI) and the other one binds E3 ligase, while the linker brings these two parts in close proximity permitting ubiquitination and subsequent degradation of the protein. Two classes of compounds were studied: pyrrolopyrimidine and thienopyrimidine derivatives. Both classes of compounds were reported in the literature and their structure is modified in order to investigate whether linker introduction deteriorate binding of those molecules to Hsp90.