Community Research and Development Information Service - CORDIS

FP7

NRF24NDDS Report Summary

Project ID: 322156
Funded under: FP7-PEOPLE
Country: Spain

Final Report Summary - NRF24NDDS (Non-conventional target approach for drug discovery against neurodegenerative diseases: Nrf2 upregulation)

Neurodegenerative diseases (NDDs) are a major worldwide health problem. These pathologies currently afflict more than 60 million people, and this number is expected to increase to 150 million by 2050. Although the primary causes of these pathologies are unknown for most of them, increasing consensus points out oxidative stress, inflammation and abnormal immune response as potential targets to develop a disease-modifying drug. Focusing on oxidative stress damage, cells have an intrinsic response to massive production of free radicals, the Nrf2-ARE pathway. Nrf2 is the transcriptional factor that regulates the “phase II antioxidant response” leading to expression of many antioxidant and neuroprotective enzymes. In this project, we proposed the development of new dual compounds capable of simultaneously reduce free radical production and to induce the Nrf2 antioxidant response in order to recover the redox equilibrium and reduce neuronal loss in NDDs.
The second period of the Marie Curie CIG project Nrf24NDDs has led to the synthesis and biological evaluation of three families of compounds complementary to those obtained in the first period. These families have been divided into three different core structures. The first structures included dual inhibitors of GSK3β (enzyme involved in tau hyperphosphorylation in Alzheimer’s disease) and AChE (an enzyme that hydrolyses acetylcholine) in a single molecule with IC50 in the submicromolar range, an activity that has been improved compared to the previous results. Furthermore, they have demonstrated a moderate Nrf2 induction capability and neuroprotective effect against two in vitro models of oxidative stress. These families have led to two patent applications and two research articles. The second structure was designed to implement two main complementary activities, Nrf2 induction and free radical scavenging properties. We have obtained two different families of derivatives that are Nrf2 inducers, highly potent free radical scavengers and good neuroprotective compounds. These families have been protected in an Spanish patent application further extended to PCT international application and the results have been described in four research articles and three new articles are under preparation. Furthermore, based on this results we have obtained financial support for initial preclinical development of our lead compound.
The interdisciplinary nature of the project includes experimental approaches in medicinal chemistry, organic chemistry, biochemistry, neurosciences, pharmacology and molecular modelling, thus favouring the generation of new knowledge with potential therapeutic application to NDDs. This also has lead to the training of technicians, master students, Ph.D. students and postdoctoral researchers on the different aspects of a multidisciplinary drug development project. Over the first period of the project, 7 Master students were well-trained in organic chemistry, biology, biochemistry and molecular modelling due to the multiple collaborations and multidisciplinary skills generated by the fellow. Final outcome of this training has led to the obtention of three Spanish government fellowships for Ph.D. thesis and 4 academic and industrial positions.
The Marie Curie CIG grant awarded to Dr. Rafael León has led to the development of the research project proposed, providing interesting and original scientific results. Furthermore, the CIG project has helped Dr. León to be integrated at the Sanitary Research Institute of University Hospital La Princesa and in the Universidad Autónoma de Madrid as a young researcher. The integration has been complemented with teaching and training activities at both institutions. As a result, thanks to the Marie Curie CIG financial support, Dr. León has created a new research group in medicinal chemistry, allowing him to continue his research as an independent scientist. Dr. León has successfully completed the first period of his career integration and he has obtained the best marks in the final evaluation. Currently, he holds a research associate position and will obtain a full position in the following three years.

Contact
LEON, Rafael (Research Fellow)
Tel.: +34-91-4972766
Fax.:+34-91-4973453
E-mail: rafael.leon@uam.es
INSTITUTO DE INVESTIGACIÓN SANITARIA HOSPITAL LA PRINCESA
Instituto Teófilo Hernando, Dpto. Farmacología y Terapéutica, Universidad Autónoma de Madrid
C/ Arzobispo Morcillo, 4
28029, Madrid
Spain

Contact

Rosario Ortiz de Urbina Barba, (Account administrative)
Tel.: +34915202476
Fax: +34915202560
E-mail

Subjects

Life Sciences
Record Number: 197064 / Last updated on: 2017-04-07
Follow us on: RSS Facebook Twitter YouTube Managed by the EU Publications Office Top