H2020Индивидуална стипендия2020–2022

RECOBIN-PROTACs · Reversible Covalently Binding PROTACs Technology for Protein Degradation in Cancer Therapy

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

Период: 2020-04-01 → 2022-03-31
Финансиране от ЕС: 224 934 €
Участници: 1
Схема: MSCA-IF-EF-ST

Линиите свързват координатора с партньорите.

Накратко на български

Нови химически инструменти, наречени RECOBIN-PROTACs, се тестват за разграждане на протеина BRD4, който стимулира растежа на клетките при остра миелоидна левкемия. Този подход цели да намали страничните ефекти и да преодолее лекарствената резистентност при лечението на 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

Reversible Covalently Binding PROTACs Technology for Protein Degradation in Cancer Therapy

Chemical tools to selectively target cancer cells over healthy cells play a vital role in today’s modern medicine. Over the decades, cancer research focuses on the development of small molecules to inhibit the activity of proteins promoting cell proliferation. Acute myeloid leukemia (AML) is an aggressive cancer of the myeloid blood cell lineage and the treatment for AML involves the use of small molecules or monoclonal antibodies that inhibit the activity of proteins promoting leukemia cell proliferation. The drug dose required for efficient inhibition often leads to off-target effects. Cancerous cells can develop resistance to such drugs by developing new mutations in the target protein. In recent years, proteolysis targeting chimeras (PROTACs) technique receives much attention for therapeutic intervention by degradation of disease-causing proteins. The aim of the project was to develop new degradation approaches by incorporating new modalities on PROTACs to address the challenges associated with stabilization of ternary complex formation to reduce the degradation concentration and differentiation of isomers. The reversible covalently binding PROTACs (RECOBIN-PROTACs) consist of a target protein-ligand (JQ1 for BRD4), cereblon E3 ligase ligand (thalidomide), and a chemoselective functional group (benzaldehyde) connected through flexible linkers. The benzaldehyde group of RECOBIN-PROTAC forms a reversible covalent modification with proximal Lys residue (K91/K141) of BET protein BRD4 (near to JQ1 binding pocket) to enable the efficient degradation of BRD4 protein. The building blocks for RECOBIN-PROTAC were synthesized and the final RECOBIN-PROTACs will be explored for demonstration of their therapeutic efficacy in AML cells. Besides, another covalent electrophilic PROTAC method was developed for degradation of the cysteine-containing proteins. The irreversible covalent PROTAC consists of cereblon E3 ligase ligand and chemoselective warhead (benzyloxy pyridinium and carbonylacrylic derivatives) connected through a linker. The ultimate goal of developing these two reversible and irreversible PROTAC approaches is to meet the broad targeting of druggable as well as undruggable proteomes.

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

Цел на проекта

Today's challenge for modern medicine is the development of tools that can selectively target cancer cells over healthy cells. Acute myeloid leukemia (AML) is an aggressive blood cancer of the myeloid cells causing bone marrow failure. Drug development research uses small molecules to inhibit the activity of proteins promoting cell proliferation. The higher concentrations of drug required for efficient inhibition often lead to off-target effects. Recent years, proteolysis targeting chimeras (PROTACs) technique receives much attention for therapeutic intervention by degradation of disease-causing proteins. However, the requirements of PROTACs such as high affinity and specificity ligands, poor stability, cell permeability, lack of cell specificity limit the broader utility of this technique. Here, we propose a novel rational design and synthesis of reversible covalently binding PROTACs (RECOBIN-PROTACs) based on the proximity labeling. A RECOBIN-PROTAC molecule consists of target protein ligand, E3 ligase ligand and a chemoselective functional group connected through flexible linkers. The chemoselective functional group forms reversible covalent modification with proximal Lys residue of BET protein or E3 ligase. This proximity labeling enhances the binding affinity of the ligands to the targets, stabilizing protein-protein interactions in ternary complex formation. The library of RT53 based RECOBIN-PROTACs will be tested on AML cell lines to find most efficient degraders. Also, the chemoselective group masked by self-immolative linker connects with enzyme-labile group and cysteine reactive handle. The most efficient RT53 based RECOBIN-PROTACs will be conjugated site-selectively to cysteine antibody to generate stable RECOBIN-PROTAC-Antibody Conjugates. These conjugates selectively release the active RECOBIN-PROTAC inside the target cells upon protease cleavage. The features of RECOBIN-PROTACs technology will bring new modalities in therapies and drug discovery.

Оригинален текст от CORDIS (на английски).

Участници

THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE · CAMBRIDGEКоординаторОбединеното кралство