Proteasomal recruiters of PAX3-FOXO1 Designed via Sequence-Based Generative Models

Duke University, Durham NC

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Abstract

Abstract Fusion-positive alveolar rhabdomyosarcoma (FP-ARMS), one of the most fatal childhood cancers, is primarily dependent on the PAX3-FOXO1 fusion oncoprotein, a chimeric transcription factor that hijacks normal gene expression and chromatin state. The five-year survival for children with PAX3-FOXO1-positive ARMS is ~30% and <10% when metastatic. PAX3-FOXO1 is largely considered an undruggable protein, with no small molecule developed to bind and inhibit its activity. Recently, we have developed novel algorithms to design specific peptides that selectively bind and degrade pathogenic proteins, including classically “undruggable” transcription factors and fusion oncoproteins. In this proposal, we will ensemble our state-of-the-art generative models to de novo design high-affinity peptide-guided degraders selective to PAX3-FOXO1 (and not PAX3 or FOXO1) and demonstrate degradation within in vitro models of FP-ARMS. The outcomes of this work will motivate downstream in vivo studies and accelerate protein-targeting medicines for FP-ARMS.