2-[[2-[[2-[(9-oxo-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-7-yl)oxy]acetyl]amino]acetyl]amino]acetic acid

General Description

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/A_2A/A_2B/A₃, or a panel of 12 cellular kinases. Selectively reduces cellular Ubc12-NEDD8, but not Ubc9-SUMO or Ubc10-Ub, thioester formation (IC_max = 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 μM) in vitro and in murine xenograft models (30 to 60 mg/kg via s.c.) in vivo via apoptosis induction.

Biochem/physiol Actions

Cell permeable: yes