Approaches to targeting RNA splicing. (A) SF3b binding agents physically interact with the branch-point binding pocket of SF3B1, thus blocking its binding with the branch point (i). Specific mutant residues in SF3B1 and PHF5A confer drug resistance to SF3b-binding agents (ii). (B) RBM39 degraders link the E3 ubiquitin ligase complex to RBM39 through the adaptor protein DCAF15, leading to polyubiquitination and subsequent proteosomal degradation of RBM39. Splicing factor–mutant leukemic cells are preferentially sensitive to RBM39 degradation. (C) PRMT5 inhibitors inhibiting PRMT5-mediated symmetric demethylation of arginines (SDMA) on Sm (D1, B/B, D3) proteins, which is required for spliceosome assembly (i). PRMT1 mediates asymmetric demethylation of arginines (ADMA) on RMB15, an RNA-binding protein regulating RNA splicing, among many additional splicing factors. Methylated RBM15 is targeted for polyubiquitination and proteosomal degradation, leading to aberrant splicing (ii). Type 1 PRMT inhibitors may prevent mis-splicing through dampening RBM15 degradation (ii). (D) Elevated R-loop formation in mutant splicing factor cells results in activation of ATR signaling pathway and DNA-damage response. Leukemic cells harboring splicing factor mutations preferentially respond to ATR inhibition. (E) ASOs complementary to the poison exon of Brd9 correct aberrant inclusion of the poison exon (i). ASOs block EJC deposition site on mRNA and prevent recruitment of the EJC downstream of a PTC, thereby preventing NMD induced by splicing factor mutations (ii).