Table 2.
Mode of action of current small-molecule modulators of the Hippo pathway.
| Compounds | Targets | Effects | Refs |
|---|---|---|---|
| Verteporfin | YAP | Inhibits YAP-TEAD interaction and transcriptional activity in vitro; suppresses hepatomegaly and hepatocellular carcinoma caused by YAP overexpression or Nf2 deletion in mouse livers | 194 |
| 9E1 | MST1 | Inhibits MST1 kinase activity in vitro and in Hela cells; has significant but incomplete selectivity and also inhibits GSK3β and PIM1 | 213 |
| LPA, S1P, thrombin | LPA-, S1P-and thrombin receptors (GPCRs) | Signal through the Gα proteins G12/13 to activate RHO and actin, which inhibits LATS kinase activity, thereby causing the dephosphorylation of YAP and TAZ. This promotes the stability and nuclear accumulation of YAP and TAZ, resulting in enhanced target gene expression, cell proliferation and cell migration in different cell lines | 102–104 |
| Epinephrine, glucagon, dihydrexidine (agonist for dopamine receptors) | GPCRs | These molecules signal through GPCRs that signal through the Gα protein Gs, cAMP, PKA, RHO and actin to activate LATS, which results in the phosphorylation of YAP and inhibition of its function in cultured cells. Injection of epinephrine into mice results in enhanced phosphorylation of YAP in the heart — the physiological target of epinephrine | 102,221 |
| Dobutamine | β-adrenergic receptor agonist | Causes YAP Ser127 phosphorylation, cytoplasmic accumulation and suppression of YAP-TEAD transcriptional activity in vitro | 222 |
| Dasatinib | Tyrosine kinase inhibitor | Suppresses proliferation of β-catenin-active cell lines in vitro; this suppression depends on the inhibition of YES1 and resulting inactivation of the YAP–β-catenin–TBX5 complex. Inhibits the growth of Apc-null colon organoids and suppresses intestinal hyperplasia of Axin1-mutant zebrafish | 55 |
| Latrunculin A, latrunculin B, cytochalasin D | F-actin | All of these actomyosin cytoskeletal drugs inhibit YAP nuclear localization as well as YAP and TEAD activity in various cell lines | 97,99–101 |
| Blebbistatin | Non-muscle myosin | Inhibits YAP nuclear localization as well as YAP and TEAD activity in various cell lines | – |
| ML7 | MLCK | Inhibits YAP nuclear localization as well as YAP and TEAD activity in various cell lines | – |
| Botulinum toxin C3 | RHO | Inhibits YAP nuclear localization as well as YAP and TEAD activity in various cell lines | – |
| Y27632 | RHO kinase | Inhibits YAP nuclear localization as well as YAP and TEAD activity in various cell lines | – |
Apc, adenomatous polyposis coli; Axin1, gene encoding axis inhibition protein 1; cAMP, cyclic AMP; GPCR, G protein-coupled receptor; GSK3β glycogen synthase kinase 3β; LATS, large tumour suppressor homolog 1; LPA, lysophosphatidic acid; MLCK, myosin Light chain kinase; MST1, mammalian STE20-like protein kinase 1; NF2, neurofibromin 2; PKA, protein kinase A; S1P, sphingosine-1-phosphate; TAZ, transcriptional co-activator with PDZ-binding motif; TBX5, T-box transcription factor 5; TEAD, TEA domain-containing sequence-specific transcription factor; YAP, Yes-associated protein.