TY - JOUR TI - Targeting RNA:protein interactions with an integrative approach leads to the identification of potent YBX1 inhibitors AU - El Hage, Krystel AU - Babault, Nicolas AU - Maciejak, Olek AU - Desforges, Bénédicte AU - Craveur, Pierrick AU - Steiner, Emilie AU - Rengifo-Gonzalez, Juan Carlos AU - Henrie, Hélène AU - Clement, Marie-Jeanne AU - Joshi, Vandana AU - Bouhss, Ahmed AU - Wang, Liya AU - Bauvais, Cyril AU - Pastré, David A2 - Faraldo-Gómez, José D A2 - Dötsch, Volker A2 - Ben-Tal, Nir VL - 12 PY - 2023 DA - 2023/01/18 SP - e80387 C1 - eLife 2023;12:e80387 DO - 10.7554/eLife.80387 UR - https://doi.org/10.7554/eLife.80387 AB - RNA-protein interactions (RPIs) are promising targets for developing new molecules of therapeutic interest. Nevertheless, challenges arise from the lack of methods and feedback between computational and experimental techniques during the drug discovery process. Here, we tackle these challenges by developing a drug screening approach that integrates chemical, structural and cellular data from both advanced computational techniques and a method to score RPIs in cells for the development of small RPI inhibitors; and we demonstrate its robustness by targeting Y-box binding protein 1 (YB-1), a messenger RNA-binding protein involved in cancer progression and resistance to chemotherapy. This approach led to the identification of 22 hits validated by molecular dynamics (MD) simulations and nuclear magnetic resonance (NMR) spectroscopy of which 11 were found to significantly interfere with the binding of messenger RNA (mRNA) to YB-1 in cells. One of our leads is an FDA-approved poly(ADP-ribose) polymerase 1 (PARP-1) inhibitor. This work shows the potential of our integrative approach and paves the way for the rational development of RPI inhibitors. KW - YBX1 KW - RNA-binding proteins KW - small molecules KW - molecular dynamics KW - free energy simulations KW - microtubule bench KW - NMR JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -