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Beschreibung

A cell-permeable AMP mimetic that targets the NEDD8-activating E1 enzyme NAE nucleotide-binding site and undergoes a NAE-catalyzed covalent NEDD8 adduct formation, the adduct in turn acts as a tight-binding, ATP-competitive NAE inhibitor (IC50 = 4.7 nM), exhibiting much reduced or little potency against Ub-activating enzyme UAE/UBA1, Ub-like modifier activating enzyme UBA6/UBE1L2, SUMO activating enzyme SAE, Ub-like modifier activating enzyme ATG7 (IC50 = 1.5, 1.8, 8.2, and >10 µ,M, respectively), adenosine receptors A1/A2A/A2B/A3, or a panel of 12 cellular kinases (IC50 >10 µ,M). Selectively reduces cellular Ubc12-NEDD8, but not Ubc9-SUMO or Ubc10-Ub, thioester formation (ICmax = 90 nM in HCT-116 cultures in 24 h), resulting in build-up of CRLs (cullin-RING ligases) substrates CDT1, NFE2L2/NRF2, and p27, without affecting overall cellular protein turnover. Shown to inhibit the growth of cancers of various origins both in cultures (IC50 from 50 nM to 1.03 µ,M) in vitro and in murine xenograft models (30 to 60 mg/kg, q.d. or b.i.d via s.c.) in vivo via apoptosis induction., A cell-permeable AMP mimetic that targets the NEDD8-activating E1 enzyme NAE nucleotide-binding site and undergoes a NAE-catalyzed covalent NEDD8 adduct formation, the adduct in turn acts as a tight-binding, ATP-competitive NAE inhibitor (IC50 = 4.7 nM), exhibiting much reduced or little potency against UAE/UBA1, UBA6/UBE1L2, SAE, ATG7, adenosine receptors A1/A2A/A2B/A3, or a panel of 12 cellular kinases. Selectively reduces cellular Ubc12-NEDD8, but not Ubc9-SUMO or Ubc10-Ub, thioester formation (ICmax = 90 nM in HCT-116 cultures in 24 h), resulting in cullin-RING ligases substrates elevation. Shown to inhibit the growth of various cancer cells both in cultures (IC50 from 50 nM to 1.03 µ,M) in vitro and in murine xenograft models (30 to 60 mg/kg via s.c.) in vivo via apoptosis induction.