Molecular editing, rooted in synthetic chemistry, has emerged as a powerful tool for structure optimization in medicinal chemistry but remains underutilized in targeted protein degradation. Here, we demonstrate the utility of molecular editing by repurposing the NSD2 degrader LLC0424 with GSPT1 neosubstrate engagement to generate two structurally analogous molecules with divergent modes of action: 424-ND, a PROTAC selective for NSD2, and 424-GD, a selective GSPT1 molecular glue. 424-ND drove NSD2 degradation selectively in a CRBN- and proteasome-dependent manner and functionally suppressed androgen receptor (AR) signaling in prostate cancer cells. 424-GD induced selective degradation of GSPT1 and robustly upregulated the integrated stress response markers ATF4 and ATF3. Biolayer interferometry revealed distinct ternary complex cooperativity profiles in the presence of NSD2 or GSPT1, which directly correlate with the observed biased degradation activity. Further molecular dynamics and metadynamics simulations showed that the compounds adopt distinct low-energy conformational ensembles with different spatial orientations, likely underlying their divergent cooperativity and selectivity. These findings not only deliver highly selective chemical probes for NSD2 and GSPT1 but also demonstrate that molecular editing enables precision control over target selectivity, providing a generalizable strategy to tune selectivity in targeted protein degradation. Table of Contents Graphic
Wei-Zhong Shen, Yi-Han Liu, Lian-Chao Liu et al.· bioRxiv· 0 citations
Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer and is characterized by substantial clinical heterogeneity, highlighting the need for reliable prognostic biomarkers. This study evaluated the expression pattern, prognostic relevance, and immune-related associations of ARHGAP22 in ccRCC using transcriptomic and clinical data from The Cancer Genome Atlas Kidney Renal Clear Cell Carcinoma (TCGA-KIRC) cohort, together with external validation data and protein-expression information from the Human Protein Atlas (HPA). ARHGAP22 expression was compared between tumor and adjacent normal tissues, and its associations with overall survival, clinicopathological characteristics, tumor microenvironment scores, and estimated immune-cell fractions were assessed. Co-expression and functional-enrichment analyses were also performed to characterize potential biological associations. ARHGAP22 was significantly upregulated in ccRCC tissues at the transcriptomic level, with corresponding differences observed in immunohistochemical images. High ARHGAP22 expression was associated with shorter overall survival, advanced clinicopathological features, and higher ImmuneScore, StromalScore, and ESTIMATEScore values. CIBERSORT-based analysis showed that the high-expression group had higher estimated fractions of M2 macrophages and regulatory T cells and lower estimated fractions of naïve B cells, resting mast cells, and activated dendritic cells after false discovery rate correction. Functional-enrichment analyses linked ARHGAP22-associated genes to immune-related processes, cell migration, and chemokine- and cytokine-mediated signaling pathways. These findings suggest that ARHGAP22 may represent a potential prognostic and immune-related biomarker in ccRCC, although further independent clinical and experimental validation is required.
Yongzhuo Li, He Duan, Li Su et al.· Journal of Visualized Experi...· 0 citations
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