Description
Leucine-rich repeat kinase 2 (LRRK2) is an enzyme that interacts with parkin, a ligase that is part of the ubiquitin-proteasome system that mediates the targeting of proteins for degradation. Loss of function of the parkin protein leads to dopaminergic cell death. The development of Parkinson''s disease has been strongly associated with mutations in the LRRK2 gene that lead to increased kinase activity. GNE 0877 is a selective, brain-penetrable LRRK2 inhibitor (K
i = 0.7 nM). It inhibits LRRK2 Ser
1292 autophosphorylation in BAC transgenic mice expressing human LRRK2 protein with the G2019S Parkinson’s disease mutation with an IC
50 value of 3 nM
in vivo.
in vitro
gne-0877 showed significantly enhanced lrrk2 cellular potency (3 nm) and low turnover in human liver microsomes and hepatocytes with no evidence of glucuronidation. invitrogen kinase-selectivity profiling (188 kinases) of gne-0877 at 0.1 μm resulted in only four kinases showing greater than 50% inhibition and suggested that gne-0877 is a highly selective lrrk2 inhibitor. furthermore, gne-0877 possessed a 212-fold biochemical-selectivity index over ttk (ki = 150 nm) [1].
in vivo
gne-0877 was evaluated for its ability to inhibit in vivo lrrk2 ser1292 autophosphorylation using bac transgenic mice expressing human lrrk2 protein with the g2019s parkinson’s disease mutation. using free-drug concentrations, robust concentration-dependent inhibition of ser1292 autophosphorylation was observed for gne-0877 [1].
References
[1] estrada aa, chan bk, baker-glenn c, beresford a, burdick dj, chambers m, chen h, dominguez sl, dotson j, drummond j, flagella m, fuji r, gill a, halladay j, harris sf, heffron tp, kleinheinz t, lee dw, le pichon ce, liu x, lyssikatos jp, medhurst ad, moffat jg, nash k, scearce-levie k, sheng z, shore dg, wong s, zhang s, zhang x, zhu h, sweeney zk. discovery of highly potent, selective, and brain-penetrant aminopyrazole leucine-rich repeat kinase 2 (lrrk2) small molecule inhibitors. j med chem. 2014 feb 13;57(3):921-36.
