Periodic Reporting for period 1 - DETRIMODE (DEgradation TRIggered by MOdular DEsign)
Berichtszeitraum: 2018-05-21 bis 2020-05-20
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
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
From the beginning of the project, the research work mainly focused on investigating the synthetic feasibility of the designed chemical approach. Precisely, the fellow looked into specific chemical reactions applied on solid phase for the synthesis of different building blocks useful for the generation of TPDIs. The approach is novel and therefore required optimization of the conditions of reaction to obtain general synthetic methods.
DETRIMODE project resulted in the establishment of a novel methodology for the synthesis on solid phase of TPDIs. The optimized chemical reactions have been used to synthesize an array of linkers grafted on solid phase and completed with small molecule ligands able to interact with the proteasome system. This allowed the exploration of variations in the structure of the obtained building blocks in a modular manner, demonstrating the chemical scope of the developed method.
Complete new chemical entities TPDIs have been obtained reacting those building blocks with small molecule ligands of target proteins of interest in the oncology field. Also in this case conditions of reaction have been optimized exploiting the synthetic utility of the synthesized intermediates for the potential generation of library of TPDIs.
While conducting chemistry research work, the fellow started a review of the literature to identify possible proteins to be targeted with novel TPDIs once the synthetic approaches will be fully developed.
Dissemination of the obtained result has been conducted to educated audience for the entire duration of the project with the organization of seminars and lectures upon invitation at different universities. This allowed sharing the result of the DETRIMODE project to the scientific community providing a starting point for the successive diffuse exploitation of the developed methods in the field of targeted protein degradation.
DETRIMODE project resulted in the establishment of a novel methodology for the synthesis on solid phase of TPDIs. The optimized chemical reactions have been used to synthesize an array of linkers grafted on solid phase and completed with small molecule ligands able to interact with the proteasome system. This allowed the exploration of variations in the structure of the obtained building blocks in a modular manner, demonstrating the chemical scope of the developed method.
Complete new chemical entities TPDIs have been obtained reacting those building blocks with small molecule ligands of target proteins of interest in the oncology field. Also in this case conditions of reaction have been optimized exploiting the synthetic utility of the synthesized intermediates for the potential generation of library of TPDIs.
While conducting chemistry research work, the fellow started a review of the literature to identify possible proteins to be targeted with novel TPDIs once the synthetic approaches will be fully developed.
Dissemination of the obtained result has been conducted to educated audience for the entire duration of the project with the organization of seminars and lectures upon invitation at different universities. This allowed sharing the result of the DETRIMODE project to the scientific community providing a starting point for the successive diffuse exploitation of the developed methods in the field of targeted protein degradation.
Considering the growing interest in the topic of targeted protein degradation for the generation of new therapeutic agents, the results obtained with the project have a significant impact, representing advancement in the field. The developed synthetic method represents a novel approach for the synthesis of TPDIs exploiting the use of solid phase synthetic techniques, allowing the application of a possible combinatorial approach with advantages in terms of generation of diversity and synthetic feasibility. During the development of the synthetic method a type of etherification chemical reaction has been applied on solid phase for the first time, incrementing its chemical scope.
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
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