SBMB-004: A first-in-class dual MDM2/BRD4 inhibitor restoring p53 function and suppressing oncogenic transcription in acute myeloid leukemia

Acute myeloid leukemia (AML) remains difficult to treat due to relapse and therapeutic resistance driven by convergent oncogenic pathways. Overexpression of murine double minute 2 (MDM2) suppresses the tumor suppressor activity of p53, while bromodomain-containing protein 4 (BRD4) sustains oncogenic transcriptional programs; together, these mechanisms promote leukemic survival. Given the limited durability of single-pathway inhibition, we employed a structure-guided virtual screening approach using the ChemBridge library to identify dual modulators targeting the MDM2 pocket and BRD4 bromodomains. The lead compound, SBMB-004, was characterized through molecular docking, 100-ns molecular dynamics simulations, and Molecular Mechanics Poisson–Boltzmann Surface Area (MM/PBSA) binding free energy analyses, followed by biochemical and cellular validation. SBMB-004 demonstrated potent dual inhibition of MDM2 (half maximal inhibitory concentration IC₅₀ = 80.08 nmol/L) and BRD4 (IC₅₀ = 95.15 nmol/L) in time-resolved fluorescence resonance energy transfer (TR-FRET) assays. In AML cell models, it exhibited selective anti-proliferative activity with 50% growth inhibition (GI₅₀) values of 110.9 nmol/L in THP-1 (p53-WT), 356.1 nmol/L in SKM-1 (mutant p53), and 1.75 µmol/L in U937 (p53-null) cells, while sparing normal HS-5 stromal cells (GI₅₀ > 3.6 µmol/L). SBMB-004 induced time-dependent intracellular p53 stabilization in p53-competent cells and triggered apoptosis preferentially in wild-type contexts, with additional BRD4-mediated cytotoxic effects observed in p53-defective models. Collectively, these findings establish SBMB-004 as a first-in-class dual MDM2/BRD4 inhibitor and support multitargeted pathway modulation as a rational strategy to restore p53 signaling and counteract transcriptional resistance mechanisms in AML.