The tale of proteolysis targeting chimeras (PROTACs) for leucine-rich repeat kinase 2 (LRRK2)

Markella Konstantinidou, Asmaa Oun, Pragya Pathak, Bidong Zhang, Zefeng Wang, Frans ter Brake, Amalia Dolga, Arjan Kortholt, Alexander Doemling*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Here we present the rational design and the synthetic methodologies towards proteolysis targeting chimeras (PROTACs) for the recently-emerged Parkinson's target leucine-rich repeat kinase 2 (LRRK2). Two highly potent, selective and 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.

Original languageEnglish
Pages (from-to)959-965
JournalChemMedChem
Volume16
Issue number6
Early online date5-Dec-2020
DOIs
Publication statusPublished - 18-Mar-2021

Keywords

  • LRRK2
  • Cereblon
  • PROTAC
  • degradation
  • Parkinson's disease

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