Nutlin-3a-HT

Amino Acid Sequence

3D Structure (/structures/AF-Q00987-F1-model_v6.cif)

Function

E3 ubiquitin-protein ligase that mediates ubiquitination of p53/TP53, leading to its degradation by the proteasome. Inhibits p53/TP53- and p73/TP73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. Also acts as a ubiquitin ligase E3 toward itself and ARRB1. Permits the nuclear export of p53/TP53. Promotes proteasome-dependent ubiquitin-independent degradation of retinoblastoma RB1 protein. Inhibits DAXX-mediated apoptosis by inducing its ubiquitination and degradation. Component of the TRIM28/KAP1-MDM2-p53/TP53 complex involved in stabilizing p53/TP53. Also a component of the TRIM28/KAP1-ERBB4-MDM2 complex which links growth factor and DNA damage response pathways. Mediates ubiquitination and subsequent proteasome degradation of DYRK2 in nucleus. Ubiquitinates IGF1R and SNAI1 and promotes them to proteasomal degradation. Ubiquitinates DCX, leading to DCX degradation and reduction of the dendritic spine density of olfactory bulb granule cells. Ubiquitinates DLG4, leading to proteasomal degradation of DLG4 which is required for AMPA receptor endocytosis. Negatively regulates NDUFS1, leading to decreased mitochondrial respiration, marked oxidative stress, and commitment to the mitochondrial pathway of apoptosis. Binds NDUFS1 leading to its cytosolic retention rather than mitochondrial localization resulting in decreased supercomplex assembly (interactions between complex I and complex III), decreased complex I activity, ROS production, and apoptosis.

Description

In a fluorescence polarization (FP)-based assay, Nutlin-3a-HT(2) displaced a fluorophore-labeled, p53-derived peptide from MDM2 with low micromolar activity (IC50 = 2.83 0.40 μM, Ki = 1.24 0.18 μM)19 (Fig. 3) .

Description

After 48 h ofexposure, 2 had an IC50 value of10.5±2.5 μM, whereas 1 only exhibited a 41% reduction of cell viability at 30 mM (Fig. S6, ESI†). After 120 h, 2 exhibited an IC50 value of 0.83±0.17 μM, which is 2.4-fold lower compared to 1 (IC50 =2.00±0.09 μM, Fig. 5C). (B and C) Cell viability assays of HCT-116 cells after (B) 24 h, and (C) 120 h exposure to 1, 2,and 7 (n = 3). Cell viability in the presence of DMSO control was defined as 100%. Mean values and standard deviations are shown. *p o 0.05, **p o 0.01, ***p o 0.001 (t-test, two-tailed, paired).

Description

In a fluorescence polarization (FP)-based assay, Nutlin-3a-HT (2) displaced a fluorophore-labeled, p53-derived peptide from MDM2 with low micromolar activity (IC50 = 2.83 ± 0.40 μM, Ki = 1.24 ± 0.18 μM)