YAF2 Inhibitors

Chemical inhibitors of YAP2 work through various mechanisms to impede its function as a transcriptional coactivator. Chetomin and verteporfin target the interaction of YAP2 with transcriptional machinery. Chetomin disrupts the binding of YAP2 to p300/CBP, a coactivator essential for YAP2 to exert its function, while verteporfin impedes the interaction between YAP2 and TEAD transcription factors, crucial for the transcriptional activity of YAP2 in the Hippo signaling pathway. Peptide 17 binds directly to YAP2, preventing its translocation to the nucleus, which is necessary for its role in gene expression. On the other hand, IWP-2, a porcupine inhibitor, reduces the activity of the Wnt pathway, an upstream regulator of the Hippo pathway, thereby reducing the functional activity of YAP2 indirectly. XMU-MP-1 targets MST1/2 kinases, which phosphorylate YAP2, leading to its inhibition. By inhibiting MST1/2, XMU-MP-1 indirectly prevents YAP2 phosphorylation by LATS1/2, thus inhibiting YAP2 activity.

Dasatinib acts on Src family kinases, which can phosphorylate and activate YAP2; its inhibitory action on these kinases can diminish YAP2's activation and its coactivator functions. GSK-3 inhibitor IX affects YAP2 indirectly by stabilizing β-catenin, which can compete with YAP2 for TEAD binding, thus reducing YAP2-mediated transcription. Palbociclib (PD 0332991) inhibits CDK4/6, which are key for cell cycle progression, and by doing so, it indirectly influences YAP2 activity, which is known to promote cell proliferation. PF-562271, a FAK inhibitor, can alter the cytoskeletal dynamics and cellular signaling, thereby affecting the activity of YAP2. Lastly, a Lats inhibitor directly targets LATS1/2 kinases, which would normally phosphorylate and inhibit YAP2, but this inhibition can paradoxically result in reduced YAP2 activity due to the activation of negative feedback mechanisms within the Hippo pathway.