Competitive inhibitor of LRRK2
Protein target names: LRRK2
Mechanism of action: Competitive inhibitor
In Vitro Validations
In Cell Validations
In Vivo Data
SERP ratings and comments
This probe comes from a structure- and property-guided optimization of an earlier compound that was identified using a JAK2-based LRRK2-homology model. As such, JAK2 was used for selectivity standard during optimization. Having said that, most of the selectivity data in the original paper look respectable. According to Figure 6A of the original publication, a higher dose may be appropriate for oral administration than i.p.
This reviewer would use GNE7915 in the cell-based setting with caution. The reasons are several fold: 1) Only biochemical selectivity was disclosed in the paper - no translation to selectivity in cell-based systems was presented. 2) The compound is an inhibitor of the target (biochemical Ki=1 nM) and TTK (biochemical Ki=53 nM) and ALK (biochemical Ki not disclosed, but >65% probe displaced at 100 nM in the KinomeScan evaluation). 3) GNE7915 inhibits several other kinases as 100 nM (>50% probe displacement at 100 nM in KinomeScan evaluation), and the identity of these other kinases was not disclosed. 4) In a Cerep panel, GNE7915 inhibits 5-HT2B (>70% inhibition at 10 uM). GNE7915 was described as a moderately potent inhibitor of 5-HT2B after functional follow-up, but inhibition data were not supplied. For in vivo studies, this reviewer would be very selective and only evaluate in the Sprague-Dawley strain of rats. The reasons are as follows: 1) No data with other species was presented. Importantly for a related molecule (compound 1 from the J. Med. Chem. manuscript), a high degree of variation between CNS exposures in mouse and rat was noted. Thus, in the absence of any mouse data for GNE-7915, users should not try to extrapolate data to other rodent species. Indeed, as GNE7915 was evaluated in Sprague Dawley rats only, interstrain variability in rats may also be possible. 2) Upon dosing of GNE7915 in rats, no effort was made to see if inhibition of the other kinases that are known to be 'hit' by GNE7915 occurred. 3) Upon dosing of GNE-7915 in rats, no effort was made to see if inhibition of 5-HT2B occurred.
In vivo use will depend on application and delivery method: 15 mg/kg is suitable for IP, and 50 mg/kg suitable for oral delivery.