The tale of proteolysis targeting chimeras (PROTACs) for Leucine-Rich Repeat Kinase 2 (LRRK2)

Konstantinidou M., Oun A., Pathak P., Zhang B., Wang Z., ter Brake F., ...More

CHEMMEDCHEM, vol.16, no.6, pp.959-965, 2021 (Peer-Reviewed Journal) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 16 Issue: 6
  • Publication Date: 2021
  • Doi Number: 10.1002/cmdc.202000872
  • Journal Name: CHEMMEDCHEM
  • Journal Indexes: Science Citation Index Expanded, Scopus, BIOSIS, Biotechnology Research Abstracts, Chemical Abstracts Core, EMBASE, MEDLINE, Index Chemicus (IC), Current Chemical Reactions (CCR)
  • Page Numbers: pp.959-965
  • Keywords: cereblon, degradation, LRRK2, Parkinson&apos, s disease, PROTAC, HIGHLY POTENT, DISEASE, INHIBITORS, DISCOVERY, MUTATIONS, BINDING


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.