MSCA Detrimode Project
DEgradation TRIggered by MOdular DEsign (DETRIMODE) is a multidisciplinary project funded by the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 797077 (Individual Fellowship, call H2020-MSCA-IF-2017).
The project, started in 2018 and completed in 2020, was pursued within the Chemistry Department of Nerviano Medical Sciences Srl, the company of the NMS Group focused on the discovery and clinical development of new small molecule drugs for oncology. Nerviano Campus’ consolidated expertise in drug discovery and lead finding, such as its chemistry skills in solid phase synthesis methodologies have been exploited to achieve the project goal.
DETRIMODE main focus was the technology of targeted protein degradation, a research field that has been recently developed, immediately becoming one of the “hot areas” in chemical biology.
Targeted protein degradation represents an innovative therapeutic method that relies on a powerful technique for protein silencing, creating a novel paradigm for drug discovery. This technology is based on Targeted Protein Degradation Inducers (TPDIs, also called PROTAC) molecules. TPDIs are heterobifunctional 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 degrading the targeted protein, resulting in a rapid depletion of the specific protein pool.
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 highlighting the importance of the research in the field.
The aim of the DETRIMODE project was the development of a methodology platform for the design and synthesis of TPDIs. The newly developed platform mainly relied on solid phase synthetic techniques. This innovative strategy in the field of TPDIs required 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 TPDIs. 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 TPDIs targeting protein of interest in the oncology area.
The exploitation of this synthetic method could be useful to advance the field of TPDIs offering new alternative approaches for the generation of new chemical entities TPDIs. Moreover, the developed method is general and can be applied to research topic different from TPDIs field, resulting of interest to the scientific community.
Links of interest:
- A special issue from “Drug Discovery Today: Technologies” on protein degradation
- A news feature from “Nature” on TPDIs
- A brief comment on protein degradation by Derek Lowe’s blog “In the pipeline”
- A recent review on PROTAC technology published in “ACS Medicinal Chemistry Letters”
- Marie Skłodowska-Curie Actions Individual Fellowship webpage
For any information and update of the DETRIMODE project please contact firstname.lastname@example.org
This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 797077”