DNL343 is a potent, selective, and brain-penetrant eIF2B activator with IC50 of 3.2 nM in cellular ATF4 nano-Luciferase (nLuc) reporter assays.
DNL343 is highly CNS-penetrant in a rat PK study with a brain-to-plasma unbound ratio (Bu/Pu) of 0.8.
Displays no activation of PXR, CAR, or AHR, as well as no significant effect against CEREP or kinase selectivity panels.
inhibits the formation of TDP43(86–414)-positive stress granules in a dose-dependent manner in H4 cells with IC50 of 13 nM.
DNL343 inhibits ISR activation in the brain of the Eif2b5 R191H knock-in mouse model, reduces ISR markers, shows potential therapeutic for the treatment of ALS.
