In this work, published in collaboration with Boston Children's Hospital, Evotec actively contributed to the identification of DW0254 and small molecule analogs capable of inhibiting RAC activation in acute lymphoblastic leukemia cell lines. Photoaffinity labelling mass spectrometry (PALMS) approach was successfully applied to identify PDE6D as the molecular target of DW0254. PALMS and biophysical methods were also used to identify the binding site of DW0254 in PDE6D. Our study provides evidence that PDE6D-dependent RAS trafficking with downstream activation of PI3K/AKT and RAC constitutes a novel potential therapeutic target in high risk leukemias.
