H2020Индивидуална стипендия2018–2020

DETRIMODE · DEgradation TRIggered by MOdular DEsign

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2018-05-21 → 2020-07-30
Финансиране от ЕС: 168 277 €
Участници: 1
Схема: MSCA-IF-EF-SE

Линиите свързват координатора с партньорите.

Накратко на български

Молекулите TPDIs се изследват като средство за насочване на клетъчната система за разграждане към конкретни вредни протеини. Разработването на метод за техния синтез помага при създаването на нови лекарства за терапия на заболявания като рака.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

DEgradation TRIggered by MOdular DEsign

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

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

The project DETRIMODE (DEgradationTRIggered by MOdular Design) aims at the development of a methodology for the modular synthesis of Targeted Protein Degradation Inducers (TPDI), designed as bifunctional molecules apt to the degradation of target proteins via recruitment of the ubiquitin proteasome system, a process with therapeutic prospects if applied to disease driving proteins. TPDIs are comprised of an E3 ligase ligand and a target protein ligand joined by a spacer (linker), to bring the ubiquitinating system and the target protein in close proximity, so to promote degradation of the latter. The formation of the ternary complex (target protein-TPDI-E3 ligase) is an articulated process influenced by a series of factors, such as ligands affinity, linker length and composition and molecular features of the proteins involved. The project tackles this endeavour in stages of increasing innovation, progressively incrementing the scope, flexibility and efficiency of modular synthetic access to arrays of tripartite molecules via protected, solid grafted intermediates, combinable with a variety of target ligands. New chemical entities TPDIs will be generated targeting selected purinome proteins oncology-related. This project will be pursued within the Chemical Core Technologies Dept. of a fully integrated company (NMS), engaged in the discovery and development of new small molecule based drugs. Organic and solid phase chemistry, computational and structural chemistry, molecular and cell biology, among others, will be exploited to achieve the project’s goal. In such multidisciplinary environment, this new technology will grow at the same speed with the researcher’s medchem competence, increasing the chance of mutual success. DETRIMODE outcomes will be shared with peers, while updates on its progresses as well as general information on how EC-funded research have impact on the general public will be communicated by a number of means, bringing science closer to society

Оригинален текст от CORDIS (на английски).

Участници

NERVIANO MEDICAL SCIENCES S.R.L · NERVIANOКоординаторИталия