Allosteric\nActivation of Protein Phosphatase 5 with\nSmall Molecules

The activation of PP5 is essential for a variety of cellular\nprocesses,\nas it participates in a variety of biological pathways by dephosphorylating\nsubstrates. However, activation of PP5 by small molecules has been\na challenge due to its native “self-inhibition” mechanism,\nwhich is controlled by the N-terminal TPR domain and the C-terminal\nαJ helix. Here, we reported the discovery of <b>DDO-3733</b>, a well-identified TPR-independent PP5 allosteric activator, which\nfacilitates the dephosphorylation process of downstream substrates.\nConsidering the negative regulatory effect of PP5 on heat shock transcription\nfactor HSF1, pharmacologic activation of PP5 by <b>DDO-3733</b> was found to reduce the HSP90 inhibitor-induced heat shock response.\nThese results provide a chemical tool to advance the exploration of\nPP5 as a potential therapeutic target and highlight the value of pharmacological\nactivation of PP5 to reduce heat shock toxicity of HSP90 inhibitors.