De novo protein design enables targeting of intractable oncogenic interfaces

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ABSTRACT Protein-protein interactions (PPIs) involving oncogenic drivers remain among the most intractable targets in cancer biology due to their dynamic conformations and limited accessibility to conventional small molecules. Although antibodies and indirect inhibitors have achieved clinical success against targets such as PD-1/PD-L1 and MYC, challenges persist related to tissue penetration, intracellular delivery, resistance, and incomplete blockade of key interface hotspots. Here, we present DesignForge, an integrated de novo protein design framework that combines deep-learning-based structure generation, sequence optimization, and energetic hotspot mapping to create compact miniprotein binders for PPIs. Using this approach, we engineered PD-1 mimetics predicted to disrupt the PD-1/PD-L1 immune checkpoint, designed scaffolds targeting the MYC/MAX dimerization interface, and generated KRAS binders in a manner predicted to occlude RAF interaction. The top designs showed high structural confidence by AlphaFold2, favorable stability metrics, and consistent hotspot engagement identified through MOE-based analyses. Collectively, these results establish DesignForge as a generalizable in silico platform for rational design of therapeutic protein binders that extend beyond antibody and small-molecule modalities to systematically target intractable oncogenic PPIs.

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