Figure 3.

Repurposing of drugs on YAP (Yes-1 associated protein)-TEAD (transcriptional enhanced associate domain) system through cross-talking pathways. Hippo pathway core kinases (in blue) and final effector YAP are modulated by approved drugs through different cross-talking pathways. Dobutamine binds β₁-adrenergic receptor and promotes LATS (large tumor suppressor) 1/2 phosphorylation through PKA (protein kinase A) signaling, while melatonin is believed to modulate YAP through pleiotropic mechanisms (GPCRs (G-protein coupled receptors) signaling in red). Statins, as HMG-CoA (3-hydroxy-3-methylglutaryl CoA) reductase inhibitors, impair Rho signaling in orange and modulate actin cytoskeleton, impairing LATS1/2 activation altogether. Tyrosine kinase inhibitors target growth factors signaling in cerulean (PI3K-AKT pathway), green (MAPK (mitogen-activated protein kinase) pathway) and black and purple (MAPK pathway final effectors) according to the proper interested drug. Receptor autophosphorylation inhibitors, such as Gefitinib, Erlotinib, and Pazopanib, hit an ATP-binding site. Instead, Dasatinib is a Src/Bcr-abl dual inhibitor, while Losmapimod and Trametinib target downstream components of MAPK pathway. Dimethylfumarate inhibits GSK3β phosphorylation, preventing APC β-catenin destruction complex formation and undermining oncogenic β-catenin pathway in the process. Metformin, through AMPK phosphorylation and consequent half-time AMOT (Angiomotin) prolongment, promotes phosphorylation-independent YAP cytoplasmic sequestration by AMOT in yellow. Digitoxin, Verteporfin and Flufenamic acid and derivatives modulate YAP/TEAD interaction, as better discussed in paragraphs 3 and 4.