Biochem/physiol Actions

GSK′481 is a highly potent receptor interacting protein 1 kinase (RIP1, RIPK1) inhibitor (human/monkey RIP1 IC₅₀= 1.6/2.5 nM; [ATP] = 50 μM) that targets RIP1 ATP-binding pocket with high affinity (k_on = 0.66/μM/sec, t_1/2 = 11 min) with little potency toward non-primate RIP1 (IC₅₀ = 2.0/3.2/6.3/7.9/>10 μM against rabbit/mouse/rat/dog/minipig RIP1) and no off-target affinity when profiled at 10 μM by a 456-kinase panel. GSK′481 blocks caspase inhibitor/TNF-induced necroptosis in human monocytic U937 cultures (IC₅₀= 10 nM) and inhibits S166 autophosphorylation of exogenously expressed human, but not mouse, RIP1 in HEK293T transfectants (IC₅₀= 2.8 nM and >10 μM, respectively).