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Description

A cell-permeable pyrrolopyrimidamine compound that acts as a highly potent EIF2AK3/PERK inhibitor (IC50 = 0.4 nM, [ATP] = 5 µ,M) by targeting PERK in its inactive DFG conformation at the ATP-binding region, while displaying >=385-fold selectivity over c-Kit, Aurora B, BRK, HRI/EIF2AK1, MLK2/MAP3K10, c-MER, DDR2, PKR/EIF2AK2, and MLCK2/MYLK2 (IC50 = 154, 407, 412, 420, 452, 474, 524, 696, and 701 nM, respectively) and little activity against more than 280 other kinases (IC50 >1 µ,M). Shown to block ER stress-induced PERK autophosphorylation following Thapsigargin (Cat. No. 586005) addition in A549 cultures in vitro (by 100% at <=30 nM, 60 min preincubation) and effectively retard PxBC-3 tumor growth in mice in vivo (50 and 150 mg/kg/12 h p.o.). Also available as a 25 mM solution in DMSO (Cat. No. 508340)., A cell-permeable pyrrolopyrimidinamine compound that acts as a highly potent inhibitor against EIF2AK3/PERK-catalyzed EIF2alpha Ser51 phosphorylation in kinase assays (IC50 = 0.4 nM, 30 min preincubation, [ATP] = 5 µ,M) as well as ER stress-induced PERK autophosphorylation following Thapsigargin (Cat. No. 586005) addition in A549 cultures (by 100% with <=30 nM inhibitor, 60 min preincubation) by targeting PERK in its inactive conformation at the ATP-binding region. Displays >=385-fold selectivity over c-Kit, Aurora B, BRK, HRI/EIF2AK1, MLK2/MAP3K10, c-MER, DDR2, PKR/EIF2AK2, and MLCK2/MYLK2 (IC50 = 154, 407, 412, 420, 452, 474, 524, 696, and 701 nM, respectively) and exhibits much reduced or little activity against more than 280 other kinases (IC50 >1 µ,M). Reported to be orally available in dog, mouse, and rat with good pharmacokinetics and retard the growth of established PxBC-3 tumor mass in mice in vivo (by 20% and 59% at the end of a 21 day treatment period with b.i.d. oral dosage of 50 and 150 mg/kg, respectively). The preincubation time-dependent inhibition, extremely slow dissociation rate, as well as the observed PERK selectivity, are all consistent with the inhibitor targeting PERK in its inactive DFG conformation.