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The tale of proteolysis targeting chimeras (PROTACs) for Leucine‐Rich Repeat Kinase 2 (LRRK2)
Author(s) -
Konstantinidou Markella,
Oun Asmaa,
Pathak Pragya,
Zhang Bidong,
Wang Zefeng,
ter Brake Frans,
Dolga Amalia M.,
Kortholt Arjan,
Dömling Alexander
Publication year - 2021
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202000872
Subject(s) - proteolysis , kinase , protein kinase a , lrrk2 , microbiology and biotechnology , biology , protein degradation , cereblon , biochemistry , computational biology , chemistry , ubiquitin , enzyme , ubiquitin ligase , gene , mutation
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.