Identification of a small molecule splicing inhibitor targeting UHM domains. (4th October 2021)

• Record Type: Journal Article
• Authors: Kobayashi, Asaki; Clément, Marie‐Jeanne; Craveur, Pierrick; El Hage, Krystel; Salone, Jean de Matha; Bollot, Guillaume; Pastré, David; Maucuer, Alexandre
• Is Part Of: FEBS journal. Volume 289:Number 3(2022)
• Page Start: 682
• Page End: 698
• Publication Date: 2021-10-04
• Subjects: SF3b1 -- splicing -- splicing inhibitor -- U2AF homology motif -- U2AF2; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pathology, Molecular -- Periodicals; 572
• DOI: 10.1111/febs.16199
• Languages: English
• ISSNs: 1742-464X

Abstract

Abstract : Splicing factor mutations are frequent in myeloid neoplasms, blood cancers, and solid tumors. Cancer cells harboring these mutations present a particular vulnerability to drugs that target splicing factors such as SF3b155 or CAPERα. Still, the arsenal of chemical probes that target the spliceosome is very limited. U2AF homology motifs (UHMs) are common protein interaction domains among splicing factors. They present a hydrophobic pocket ideally suited to anchor small molecules with the aim to inhibit protein–protein interaction. Here, we combined a virtual screening of a small molecules database and an in vitro competition assay and identified a small molecule, we named UHMCP1 that prevents the SF3b155/U2AF 65 interaction. NMR analyses and molecular dynamics simulations confirmed the binding of this molecule in the hydrophobic pocket of the U2AF 65 UHM domain. We further provide evidence that UHMCP1 impacts RNA splicing and cell viability and is therefore an interesting novel compound targeting an UHM domain with potential anticancer properties. Abstract : Molecules targeting the splicing machinery are promising tools to fight tumor cells. Using a pharmacophoric bioinformatics approach, we identified the small molecule, UHMCP1, which binds the UHM domain of the essential splicing factor U2AF 65, and competes with its natural partner SF3b1. Structural analyses reveal the binding mode of UHMCP1, which we show can induce splicing changes in cells. Further research will aim to define the therapeutic potential of UHMCP1.