Fragment-based drug discovery of triazole inhibitors to block PDEδ-RAS protein-protein interaction.
Basic Information
ID: ALA4411282
Journal: Eur J Med Chem
Title: Fragment-based drug discovery of triazole inhibitors to block PDEδ-RAS protein-protein interaction.
Authors: Chen D, Chen Y, Lian F, Chen L, Li Y, Cao D, Wang X, Chen L, Li J, Meng T, Huang M, Geng M, Shen J, Zhang N, Xiong B.
Abstract: Although mutated Ras protein is well recognized as an important drug target, direct targeting Ras has proven to be a daunting task. Recent studies demonstrated that Ras protein needs PDEδ to relocate to plasma membrane to execute its signaling transduction function, which provides a new avenue for modulating the Ras protein. To find small molecules antagonizing the interactions between PDEδ and Ras, here we presented a successful application of fragment-based drug discovery of PDEδ inhibitors. Under the guidance of crystal structures, we are able to quickly optimize the initial fragment into highly potent inhibitors, with more than 2000-fold improvement in binding activity, which further adds to the arsenal towards the inhibition of Ras signaling in cancer therapy.
CiteXplore: 30562696
DOI: 10.1016/j.ejmech.2018.12.018
Patent ID: ┄