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

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
JournalChemMedChem
DOIs
Publication statusE-pub ahead of print - 5-Dec-2020

Keywords

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

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