Identification, Mechanism of Action, and Antitumor Activity of a Small Molecule Inhibitor of Hippo, TGF-β, and Wnt Signaling Pathways

Abstract

Embryonic signaling pathways, in particular those mediated by Wnt and TGF-b, are known to play key roles in tumor progression through the induction of epithelial-mesenchymal transition (EMT). Their simultaneous targeting could therefore represent a desirable anticancer strategy. On the basis of recent findings that both Wnt and TGF-b-associated pathways are regulated by Hippo signaling in mammalian cells, we reasoned that targeting the latter would be more effective in inhibiting EMT. In a search for such inhibitors, we identified a small molecule (C19) with remarkable inhibitory activity not only against Hippo, but also against Wnt and TGF-b pathways. C19 inhibited cancer cell migration, proliferation, and resistance to doxorubicin in vitro, and exerted strong antitumor activity in a mouse tumor model. Mechanistically, C19 induced GSK3-b-mediated degradation of the Hippo transducer TAZ, through activation of the Hippo kinases Mst/Lats and the tumor suppressor kinase AMPK upstream of the degradation complex. Overall, this study identified C19 as a multi-EMT pathway inhibitor with a unique mechanism of action. The findings that both AMPK and Mst/Lats mediate the antitumor activity of C19 shed light on a potential cross-talk between metabolic and organ size control pathways in regulating cancer progression. By simultaneously targeting these two pathways, C19 may represent a new type of agents to suppress cancer progression and/or its recurrence.

Inhibition of YAP/TAZ Activity in Spinal Cord Suppresses Neuropathic Pain

“…Therefore, a drug that inhibits YAP/TAZ may have a potent analgesic effect. We have proven that VP, which impedes YAP-TEAD association and inhibits YAP activity (LiuChittenden et al, 2012), is a potent analgesic, supporting the idea that VP, a prescriptive medicine currently used in clinic for treating macular degeneration (Brown et al, 2006), may also be used for treating neuropathic pain. Excitingly, we have further identified a small molecule, dCTB, and shown that it may be the most potent analgesic in treating neuropathic pain.…”

“…In the nucleus, TEAD families of transcriptional factors are known to mediate YAP/TAZ activities (Hansen et al, 2015). VP, a prescriptive medicine currently used in the clinical setting for treating macular degeneration (Brown et al, 2006), has the capability of impeding the YAP-TEAD association and causing inhibition of YAP activity (Zhao et al, 2008;Liu-Chittenden et al, 2012). We therefore tested whether VP could impede neuropathic pain.…”

“…We tested the possible analgesic effect of dCTB in CCI rats in vivo. Because the chemical synthetic pathway described in the only existing report (Basu et al, 2014) did not lead to an effective synthesis of dCTB, we thus explored and developed a more efficient, new chemical synthetic pathway to produce such a molecule. The new chemical synthetic pathway of dCTB is shown in Figure 5A.…”

“…Excitingly, we have further identified a small molecule, dCTB, and shown that it may be the most potent analgesic in treating neuropathic pain. dCTB is an existing antitumor small molecule and was reported as an inhibitor of the transcriptional responses of YAP/TAZ (Basu et al, 2014). A chemical synthetic pathway of dCTB described in the only report named compound 19 (C19) (Basu et al, 2014) did not lead to an effective synthesis.…”

“…dCTB is an existing antitumor small molecule and was reported as an inhibitor of the transcriptional responses of YAP/TAZ (Basu et al, 2014). A chemical synthetic pathway of dCTB described in the only report named compound 19 (C19) (Basu et al, 2014) did not lead to an effective synthesis. We have developed a new efficient chemical synthetic pathway (Fig.…”