Plenary Lecture 14



Title: Discovering new drugs for Parkinson´s disease: from the lab to the clinical trials

Dr. Ana Martinez Gil

Biological Research Center, Spanish Council for Research, Spain
 


Lecture Summary: Parkinson's disease (PD) is the second most prevalent neurodegenerative disease and affects about 1% of the global population over 60 years of age. PD is characterized by a combination of motor and non-motor symptoms, including psychiatric and cognitive disorders. The main pathochemical hallmark of PD is the loss of dopamine in the striatum being aging the strongest risk factor for brain degeneration. Up to date pharmacological treatment has focused on restoring dopaminergic neurotransmission and improving motor symptoms. However, the current medications do not interfere with the progressive death of dopaminergic neurons having several major limitations including side effects such as dyskinesias. As life expectancy is increasing, over the next few years the number of patients with PD will grow exponentially, being a social need to find an effective therapeutic intervention such neuroprotectant treatments that slow and/or stop disease progression and reduce both side effects and the occurrence of the very disabling clinical symptoms seen in late-stage PD.1

            With the aim to discover new drugs for PD, we have used a reverse chemical genetics strategy using our in-house chemical library and a well established cell based PD model. Several hits were found including well-known therapeutic agents for PD such as antioxidants or adenosine A2 antagonists, validating the experimental approach. Moreover, we have discovered also new targets to modulate the dopaminergic cell such different protein kinases and phosphodiesterases.2,3 After different medicinal chemistry optimization programs, glycogen synthase kinase 3, casein kinase 1 and phosphodiesterase 7 (PDE7) inhibitors have shown efficacy in different murine models of PD emerging as new disease-modifying drug candidates.4
               
Specifically, we have validated PDE7 as a therapeutic target for PD using specific siRNAs5 and supporting by ARACLON biotech, we have developed our small heterocyclic molecule called S14, a selective PDE7 inhibitor to enter in clinical trials for PD. The main tasks done from the academic laboratory to full filled the dossier to obtain approval to start clinical trials will be here discussed.

 

Acknowledgments: I would like to express my gratitude to all my research team and very especially to Dr. Carmen Gil. Without her work, and the support of Dr. M Sarasa, CEO of ARACLON Biotech, the development of S14 would not be possible.

 

References: [1] Emerging drugs and targets for Parkinson’s Disease. Martinez A. and Gil C., Ed. RSC Drug Discovery  serie. ISBN 978-1-84973-617-6. Cambridge 2013.

2 Morales-García, J.A.; Susín, C.; Alonso-Gil, S.; Pérez, D.I.; Palomo, V.; Pérez, C.; Conde, S.; Santos, A.; Gil, C.; Martínez, A.; Pérez-Castillo, A. ACS Chem Neurosci. 2013, 4, 350..

3 García, A.M.; Redondo, M.; Martinez, A.; Gil, C. Curr Med Chem. 2014, 21, 1171.

4 Morales-Garcia, J.A.; Alonso-Gil, S.; Gil, C.; Martinez, A.; Santos, A.; Perez-Castillo, A. Stem Cells Transl Med. 2015, 4, 564.

5 Morales-Garcia, J.A.; Aguilar-Morante, D.; Hernandez-Encinas, E.; Alonso-Gil, S.; Gil, C.; Martinez, A.; Santos, A.; Perez-Castillo, A. Neurobiol Aging. 2015,  36, 1160.