Single-Cell Transcriptomic Drug Repurposing in Ulcerative Colitis Identifies a Dominant MDM2 Inhibitor Cluster and Novel Candidates Including R-547, GW-9662, and TAK-733

This preprint reports a computational drug repurposing pipeline applied to GSE231993, a single-cell RNA sequencing dataset comprising colonic biopsies from 4 UC patients (inflamed), 4 UC self-controls (non-inflamed paired), and 4 healthy controls. scVI dimensionality reduction, Leiden clustering (12 colon cell types including colonocytes, goblet cells, plasma cells, macrophages, and T cells), and Wilcoxon differential expression comparing UC vs HC globally and across epithelial, immune, plasma cell, and pro-UC cluster subsets were combined with LINCS L1000 transcriptomic reversal scoring across 33 independent Enrichr queries. PubMed novelty filtering identified 303 NOVEL_ALL candidates (56%) with no prior published association with UC, IBD, or colonocyte/IL-13 biology. Top candidates: AMG-232 (MDM2, 815,012), SAR405838 (MDM2, 787,447), R-547 (CDK, 570,989), RG-7388 (MDM2, 466,170), GW-9662 (PPARγ antagonist, 377,523), TAK-733 (MEK1/2, 307,363), LXR-623 (LXR agonist, 49,934). Five MDM2 inhibitors in the top 15 candidates constitute the densest single-mechanism NOVEL_ALL cluster across the inventor's series of ten independent scRNA-seq drug repurposing analyses, implicating a p53-MDM2-colonocyte differentiation axis in UC pathogenesis. R-547 achieves four-pipeline NOVEL_ALL consistency across UC colon, MS CSF, AIHA bone marrow, and atopic dermatitis skin. LXR-623 achieves two-pipeline NOVEL_ALL consistency. Code: github.com/glenritschel/uc-scrna.