Discovery of a Phenylalanine‐Derived Natural Compound as a Potential Dual Inhibitor of MDM2 and MDMX

P5, a novel phenylalanine-derived compound isolated from Micromonospora sp. MS-62, exhibits dual inhibition of MDM2 and MDMX. Molecular docking and SPR confirm its nanomolar affinity and sustained binding kinetics. In silico profiling reveals high GI absorption, BBB permeability, and drug-likeness, highlighting its potential as a lead for p53-targeted cancer therapy.

Dual inhibition of the negative p53 regulators MDM2 and MDMX has emerged as an effective strategy in p53-based anticancer therapy. However, dual inhibitors are limited, and many inhibitors exhibit poor pharmacokinetic properties and fast dissociation kinetics. Among newly identified microbial metabolites, the novel phenylalanine-derived compound P5 isolated from Micromonospora sp. MS-62 (FBCC-B8445) exhibits inhibitory activity against both MDM2 and MDMX. The binding of P5 to MDM2 and MDMX is demonstrated by surface plasmon resonance, which reveals nanomolar-level affinity and slow dissociation kinetics (KD = 46 nM for MDM2; 576 nM for MDMX). This dual inhibitory activity was further supported by molecular docking, which reveals binding of P5 to the p53-binding pockets of both MDM2 and MDMX through extensive noncovalent interactions. In cell-based assays, P5 reduced cancer cell viability across several human cell lines. Furthermore, in silico analysis indicates favorable pharmacokinetic properties, including gastrointestinal absorption, blood–brain barrier permeability, and compliance with Lipinski's and Veber's criteria. P5 combines dual-target engagement with binding persistence and favorable pharmacokinetic characteristics, addressing limitations of earlier inhibitors. P5 is a potential lead compound for the development of MDM2/MDMX-targeted anticancer agents.

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