Fig 1: Surface plasmon resonance analysis of A,B) MDM2 and C,D) MDMX binding by (B,D) P5 and the (A,C) reference compound Nutlin‐3, with sensorgram traces represented as dotted lines and fitted curves as solid lines.
Fig 2: Fabrication of N201-gal, stable, and inhibitory MDM2 proteins. (A) Transmission electron microscopy (TEM) image showing that the stability of N201-gal depends on day and pH. (B) N201-gal diameter does not change during the 22nd day in water, 100 μM. (C) The pH changed from acidic to neutral, and the diameter slightly increased from 20 nm to 50 nm. (D) In the simulated gastric fluid and intestinal fluid, N201-gal was stable, and the diameter ranged from 20 nm to 50 nm. (E) High-performance liquid chromatography (HPLC) analysis of the stability of N201-gal at the 10.5-min peak. (F) Scheme of N201-gal cleavage to N201 by the β-galactosidase enzyme. (G) β-Galactosidase cleaves N201-gal into N201, which is present in 2 equilibriums of the enzyme. (H) Simulation of the interaction of N201 with MDM2. (I) Fluorescence polarization (FP) analysis of the interaction of N201 with MDM2 instead of with fluorescein isothiocyanate (FITC)–p53. The IC50 was 0.1302 μM. (J) FP analysis of N201-gal interacting with MDM2 instead of with FITC-p53. The IC50 was 0.2005 μM.
Fig 3: Representative MDM2 (nutlin‐3, nutlin‐3a, and RG‐7112), MDMX (RO‐5963, CTX1), and MDM2/MDMX dual inhibitors (ALRN‐6924).
Fig 4: 2D and 3D interaction diagrams of compound P5 with A,C,E) MDM2 and B,D,F) MDMX, illustrating hydrogen bonding, π–π stacking, and hydrophobic interactions. (E) and (F) display hydrophobic interaction surfaces.
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