Substituted Heterocyclic Inhibitors of YAP-TEAD and TAZ-TEAD Protein-Protein Interaction as Potential Cancer
1Arrival Discovery LLC, San Diego, California 92128, United States.
Abstract:
A series of pyrrolopyridine analogs is described as inhibitors of the YAP-TEAD, TAZ-TEAD protein-protein interaction. In recent years the Hippo pathway has become a target of interest for the treatment of disorders and diseases such as cancer. It has been established that in its "switched-on"-state the Hippo pathway involves a cascade of kinases in the cytoplasm which results in the phosphorylation of two transcriptional coactivators, YAP (Yes-associated protein) and TAZ (Transcription coactivator with PDZ binding motif). Activated YAP/TAZ binds to the transcriptional enhanced associate domain (TEAD) transcription factor family (TEAD1-4) that get activated and induce the expression of several genes, many of which mediate cell survival and proliferation. Therefore, inhibition of YAP, TAZ, TEAD, and YAP-TEAD or TAZ-TEAD protein-protein interaction appears to be a reasonable strategy to prevent and/or treat cancer associated with the dysfunction of the Hippo pathway.
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