Identification of a small molecule splicing inhibitor targeting UHM domains

International audience; Splicing factor mutations are frequent in myeloid neoplasms, blood cancers,and solid tumors. Cancer cells harboring these mutations present aparticular vulnerability to drugs that target splicing factors such asSF3b155 or CAPERα. Still, the arsenal of chemical probes that targets thespliceosome is very limited. U2AF homology motifs (UHMs) are commonprotein interaction domains among splicing factors. They present ahydrophobic pocket ideally suited to anchor small molecules with the aimto inhibit protein–protein interaction. Here, we combined a virtual screeningof a small molecules database and an in vitro competition assay andidentified a small molecule, we named UHMCP1 that prevents theSF3b155/U2AF interaction. NMR analyses and molecular dynamics simulationsconfirmed the binding of this molecule in the hydrophobic pocketof the U2AF UHM domain. We further provide evidence that UHMCP1impacts splicing and cell viability and is therefore an interesting novel compoundtargeting an UHM domain with potential anticancer properties.