The modulation of “target” protein functionality is a validated therapeutic plan for a range of diseases and drug discovery strategies are largely based on this paradigm. Recently, targeted protein degradation has been proposed as an alternative approach to inhibition for the development of new therapeutic agents.
This new methodology is based on molecules called Targeted Protein Degradation Inducers (TPDIs, also referred to as PROTAC). TPDIs are compounds that are able to interact with a target protein while hijacking the cellular proteasome system, responsible for the degradation of the protein itself. TPDIs are therefore capable of inducing degradation of the targeted protein, resulting in a rapid depletion of the specific protein pool. This research field generated huge interest by experts, immediately becoming one of the “hot areas” in chemical biology.
To date two protein degrader molecules from Arvinas Inc. are undergoing Phase I clinical trial with oncological indication. Clinical experimentation began in 2019 and represented a milestone in the development of this class of molecules for therapeutic purposes and highlight the importance of the research in the field.
The aim of the DETRIMODE project is the development of a methodology platform for the design and synthesis of TPDIs. The platform will mainly rely on solid phase synthetic techniques. This innovative strategy in the field of TPDIs will require the initial investigation of the chemical reactions involved in the solid phase synthesis of intermediates, followed by the validation of the scope of reactions.
DETRIMODE project resulted in the establishment of a novel methodology for the synthesis on solid phase of TDPIs. The developed strategy facilitates the modular synthesis of an array of advanced synthetic intermediates to be coupled with desired target protein ligands. The synthetic utility of obtained intermediates has been exploited with the synthesis of new chemical entities TDPIs targeting protein of interest in the oncology area
