Rakesh Chatrikhi, Callen F Feeney, Mary J Pulvino, Georgios Alachouzos, Andrew J MacRae, Zackary Falls, Sumit Rai, William W Brennessel, Jermaine L Jenkins, Matthew J Walter, Timothy A Graubert, Ram Samudrala, Melissa S Jurica, Alison J Frontier, Clara L Kielkopf
Dysregulated pre-mRNA splicing is an emerging Achilles heel of cancers and myelodysplasias. To expand the currently limited portfolio of small-molecule drug leads, we screened for chemical modulators of the U2AF complex, which nucleates spliceosome assembly and is mutated in myelodysplasias. A hit compound specifically enhances RNA binding by a U2AF2 subunit. Remarkably, the compound inhibits splicing of representative substrates and stalls spliceosome assembly at the stage of U2AF function. Computational docking, together with structure-guided mutagenesis, indicates that the compound bridges the tandem U2AF2 RNA recognition motifs via hydrophobic and electrostatic moieties...
February 26, 2021: Cell Chemical Biology