|
|||||
|
|
The tale of proteolysis targeting chimeras (PROTACs) for Leucine-Rich Repeat Kinase 2 (LRRK2) |
|
| Authors: | Dr Markella Konstantinidou Asmaa Oun Pragya Pathak Bidong Zhang Zefeng Wang Frans ter Brake Dr Amalia M Dolga Dr Arjan Kortholt Dr Alexander Dömling |
| Affiliation: | 1. Department of Pharmacy, Group of Drug Design, University of Groningen, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands;2. Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands
These authors contributed equally to this work.;3. Department of Cell Biochemistry, Groningen Institute of Biomolecular Sciences & Biotechnology, University of Groningen, Nijenborgh 7, 9747 AG Groningen, The Netherlands These authors contributed equally to this work.;4. Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands;5. Department of Cell Biochemistry, Groningen Institute of Biomolecular Sciences & Biotechnology, University of Groningen, Nijenborgh 7, 9747 AG Groningen, The Netherlands YETEM-Innovative Technologies Application and Research Centre Suleyman Demirel University, West Campus, 32260 Isparta, Turkey |
| Abstract: | Here we present the rational design and synthetic methodologies towards proteolysis-targeting chimeras (PROTACs) for the recently-emerged target leucine-rich repeat kinase 2 (LRRK2). Two highly potent, selective, brain-penetrating kinase inhibitors were selected, and their structure was appropriately modified to assemble a cereblon-targeting PROTAC. Biological data show strong kinase inhibition and the ability of the synthesized compounds to enter the cells. However, data regarding the degradation of the target protein are inconclusive. The reasons for the inefficient degradation of the target are further discussed. |
| Keywords: | cereblon degradation LRRK2 Parkinson's disease PROTAC |
