1402452-15-6

2-Chloro-N,N-diethyl-5-[[4-[2-[4-[[(methylamino)carbonyl]amino]phenyl]-4-pyridinyl]-2-pyrimidinyl]amino]benzenesulfonamide are pyrimidine derivatives as hSMG-1 inhibitors.

Potent and selective SMG-1 (hSMG-1; SMG1) kinase inhibitor th at blocks nonsense-mediated decay (NMD).


SMG1i is a potent and selective SMG-1 kinase inhibitor (hSMG-1 IC50 = 110 pM) with much reduced potency against mTORPI3Kα/γ and CDK1/2 (IC50 = 50 nM92/60 nM32/7.1 μMrespectively). SMG1i selectively downregulates MDA361 cellular phosphorylation of UPF1 (0.3 -1 μM)but not th at of mTOR or AKT substrates (p70s6 K and PI3K). Nonsense-mediated decay (NMD) inhibition by SMG1i (1 μM) is shown to synergize with premature termination codons (PTCs) readthrough agents (G418gentamicinand paromomycin) in promoting the expression of CFTR protein in murine cells carrying Cftr G542X nonsense mutation.

hSMG-1: 0.11 nM (IC₅₀); mTOR: 50 nM (IC₅₀); PI3Kγ: 60 nM (IC₅₀); PI3Kα: 92 nM (IC₅₀); GSKα: 260 (IC₅₀); GSKβ: 330 (IC₅₀); CDK2: 7.1 μM (IC₅₀); CDK1: 32 μM (IC₅₀)

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