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

Abstract

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.