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Benzothiazole-based LRRK2 inhibitors as Wnt enhancers and promoters of oligodendrocytic fate

AuthorsZaldívar-Díez, Josefa; Li, Lingling; García, Ana M. CSIC; Zhao, Wenning; Medina-Menendez, Cristina; Haggarty, Stephen J.; Gil, Carmen ; Morales, Aixa V. CSIC ORCID; Martínez, Ana CSIC ORCID
KeywordsLRRK2 inhibitors
Adult neurogenesis
Wnt enhancers
Oligodendrocyte differentiation
Issue Date11-Dec-2019
PublisherAmerican Chemical Society
CitationJournal of Medicinal Chemistry 63 (5) 2638-2655 (2020)
AbstractLeucine Rich Repeat Kinase 2 (LRRK2) is an enigmatic enzyme and a relevant target for Parkinson’s Disease (PD). However, despite the significant amount of research done in the last decade, the precise function of LRRK2 remains largely unknown. Moreover, the therapeutic potential of its inhibitors is in its infancy with the first clinical trial having just started. In the present work the molecular mechanism of LRRK2 in the control of neurogenesis or gliogenesis was investigated. We designed and synthesized novel benzothiazole-based LRRK2 inhibitors and showed that they can modulate the Wnt/β-catenin signaling pathway. Furthermore, compounds 5 and 14 were able to promote neural progenitors proliferation and drive their differentiation towards neuronal and oligodendrocytic cell fates. These results suggest potential new avenues for the application of LRRK2 inhibitors in demyelinating diseases in which oligodendrocyte cell-death is one of the pathological features.
Description63 p.-15 fig.-1 tab.-2 schem.
Publisher version (URL)https://doi.org/10.1021/acs.jmedchem.9b01752
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