Gene: RBM39; Protein length: ~530 amino acids (Molecular weight ~60 kDa)
Subcellular localization: Nucleus (predominantly)
Functional Roles of RBM39: Alternative Splicing (Promotes exon inclusion / exclusion by stabilizing spliceosome components at intron/exon junctions), Transcription Coactivation (Interacts with nuclear hormone receptors to modulate gene expression), RNA Processing (Bridges transcription and splicing machinery in a co-transcriptional manner).
Domain Architecture:
1. RBM39 contains two canonical RNA Recognition Motifs (RRMs): RRM1 (aa 105–180) that binds pre-mRNA and U2 snRNP components for spliceosome assembly and RRM2 (aa 200–275) that enhances binding specificity and stability; involved in splicing site selection. The two RRMs are essential for alternative splicing and co-transcriptional mRNA processing. They bind RNA substrates and interact with splicing factors like SF3B1 and U2AF65.
2. U2AF Homology Motif (UHM)-like region, which is adjacent to RRM2, mediates protein–protein interactions with other splicing factors and shares functional similarity with U2AF65, hence supports spliceosome complex assembly.
3. RS-rich Region (Arginine/Serine-rich), which is in the C-terminal region, modulates nuclear localization and splicing regulation. RS domains are found in many SR proteins and are key to splice site selection and exon inclusion.
4. The helical degron motif between aa ~250–270 is recruited to DCAF15 E3 ligase in the presence of molecular glues like indisulam or E7820. This α-helical degron fits into a hydrophobic cleft on DCAF15 in a compound-dependent manner, enabling RBM39 ubiquitination and degradation. This interaction is highly specific, and mutation of the degron confers resistance to degradation.
The degron helix and RRM domains are essential for RBM39's function and its vulnerability to proteasome-targeting therapies. Degraders like indisulam exploit RBM39’s degron for synthetic lethality in cancers dependent on splicing fidelity.
Targeting RBM39 through molecular glue degraders (e.g., E7070 / indisulam, E7820, tasisulam) has shown promise in treating cancers, particularly AML and MDS. However, these therapies also carry toxicities—some predictable due to RBM39’s essential role in RNA splicing, and others that emerged during clinical development.
On-Target Toxicities: RBM39 is critical for global mRNA splicing and transcriptional homeostasis in normal cells. Its degradation affects both malignant and non-malignant rapidly dividing cells, leading to: Myelosuppression (Anemia, neutropenia, thrombocytopenia), Hepatotoxicity (Elevated liver enzymes AST, ALT, bilirubin, etc.), Gastrointestinal toxicity (Nausea, vomiting, diarrhea), and Fatigue.
Dose-limiting toxicities (DLTs) of Indisulam (E7070) and E7820 / Tasisulam were observed in Phase I: Myelosuppression (esp. neutropenia, thrombocytopenia), Prolonged QT interval, Hepatotoxicity. Toxicity was schedule- and dose-dependent, leading to a narrow therapeutic window. Oral formulation and weekly/biweekly dosing showed better tolerability than intravenous bolus.
Ongoing efforts to improve safety include: Refining degrader specificity (e.g., enhanced DCAF15 selectivity for tumor cells), Biomarker-based stratification to identify patients more likely to benefit (e.g., those with splicing factor mutations), and Combination strategies to reduce required dosing (e.g., synergistic partners that allow lower RBM39 degrader doses).
