Fig. 1: A synthetic rescue screen identifies PRLX-93936 as inducing cell death via a ubiquitin-dependent mechanism.
From: Elaboration of molecular glues that target TRIM21 into TRIMTACs that degrade protein aggregates
a Schematic of the synthetic rescue screening strategy. Desired molecules show reduction of cytotoxicity when E1 Ubiquitin Activating Enzyme activity is impaired by the UBA1 inhibitor TAK-243, indicative of a mechanism of cell death reliant on ubiquitination. Created in BioRender. Adams, D. (2025) https://BioRender.com/66b3l1h. b Dot–plot representing the performance of 1754 bioactive small molecules in the synthetic rescue screen performed using OCI-AML-3 cells treated for 10 h. x-axis, viability measured for each library molecule with only DMSO vehicle treatment; y-axis, viability measured for each library molecule co-treated with TAK-243 (200 nM). Hits (red oval) were significantly cytotoxic as single agents (viability <50%, x-axis) and showed at least 30% greater viability in combination with TAK-243. Red circle, PRLX-93936. Each point represents data from a single well. c Structures of PRLX-93936 and erastin. d Cell viability (CellTiter-Glo) following treatment with PRLX-93936 alone or in combination with TAK-243 (200 nM) or Bortezomib (500 nM) for 10 h in OCI-AML-3 cells (n = 2 independent experiments, each with at least 2 wells per concentration). e, f Pearson correlation plots (www.depmap.org) establishing that TRIM21 expression (log2(Transcripts per million+1) is correlated with PRLX-93936 cytotoxicity (log2(Fold Change) (e) and that the cytotoxicity of PRLX-93936 and BMS-214662 is uniquely well correlated with TRIM21 among the small molecules within the database (f). Pearson correlation p-values were derived from two-sided tests with no correction for multiple comparisons. Top 1000 correlates are shown. Each correlation represents data from at least 453 cell lines. g Structures of BMS-214662 and BMS-225975. h Cell viability (CellTiter-Glo) following treatment with PRLX-93936 alone or in combination with TAK-243 (200 nM) or Bortezomib (500 nM) for 10 h in OCI-AML-3 cells (n = 2 independent experiments, each with at least 2 wells per concentration). Source data are provided as Source Data files.
