H2020Индивидуална стипендия2020–2023

Src dimerization · Activation of Src kinases through dimerization suggests novel therapeutic opportunities

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

Период: 2020-06-01 → 2023-05-31
Финансиране от ЕС: 182 722 €
Участници: 1
Схема: MSCA-IF

Линиите свързват координатора с партньорите.

Накратко на български

Ензимите NMT прикрепят протеини към клетъчните мембрани, което активира онкогена c-Src чрез свързване на две негови молекули. Разбирането на този процес помага за разработването на по-ефективни лекарства срещу рак, малария и африкански сън.

Този кратък обзор е генериран от изкуствен интелект

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

Резултати накратко

Activation of Src kinases through dimerization suggests novel therapeutic opportunities

N-myristoyltransferases (NMTs) are enzymes catalyzing the transfer of myristic acid, a 14-carbon fatty acid, to specific cellular proteins. This process, known as myristoylation, enables the anchoring of these proteins to cellular membranes. NMTs are essential for the survival of parasitic protozoan organisms and tumour cells, making them attractive targets for the treatment of devastating diseases such as malaria, African sleeping sickness, and cancer. Several NMT inhibitors have been developed and have shown promising results in preclinical models. However, despite their efficacy in these studies, these NMT inhibitors possess some undesirable pharmacological properties, such as suboptimal bioavailability and absorption, that may limit their clinical utilization. Our first objective was focused on understanding the mechanism of NMT inhibition and conducting extensive screening to identify novel NMT inhibitors with improved pharmacological properties. The results provide valuable information about the design and development of the next-generation NMT inhibitors and could give novel treatment options for malaria and oncological diseases. Our second objective was to investigate the significance of NMT-mediated myristoylation of the c-Src oncogene. Myristoylation facilitates c-Src association with cellular membranes, promotes dimerization between two Src molecules, and regulates its kinase activity. The NMT inhibitors may exert their anti-tumour activity, at least in part, by disrupting c-Src myristoylation and inhibiting its activity. However, the role of myristoylation and dimerization of c-Src in cancer remains poorly understood. Our findings revealed the deregulation of this process in cancer and that systemic activation of Src kinases plays a key role in the development of resistance mechanisms against anti-cancer therapies. Overcoming this resistant mechanism significantly improved therapy outcomes in colorectal cancer.

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

Цел на проекта

c-Src, the first proto-oncogene to be identified, controls many aspects of tumor biology including the capacity of the cancer cells to multiply, survive, and metastasize. We recently discovered that c-Src forms dimers and that dimerization is essential for the activity of the enzyme. This represents a significant paradigm shift in our understanding of the biology of Src family kinases, which until recently were assumed to function as monomeric proteins. The discovery that c-Src functions as a dimer creates the basis for development of a novel class therapeutics in principle based on disruption of Src dimerization. Our preliminary data indicate that such dimerization inhibitors have dramatic anti-tumor activity, suggesting that the proposed research may lead to development of an effective anti-cancer therapy. The project goal is to accomplish the following specific objectives: 1. To determine the efficacy of inhibition of Src myristoylation and dimerization for treatment of cancer; 2. To develop competitive inhibitors of Src dimerization and activity. The project will also create opportunities of boosting the research and innovation capacity of Europe, for obtaining IPRs, commercialization, and setting new collaborations with top US research institutions and companies. The proposal is intended as a career development fellowship that is designed to facilitate my reintegration into the EU science and to further my career towards a leading independent research position. I am confident that the quality and excellence of science produced and the new research and complementary skills obtained during the fellowship will serve as a cornerstone for my future career advancement and mark the beginning of my new laboratory and research program.

Оригинален текст от CORDIS (на английски).

Участници

MEDICAL UNIVERSITY SOFIA · SofiaКоординаторБългария