Yap1抑制剂的替代药物

Yap1抑制剂目前没有专门的靶向药上市，有一些替代药物：
一、维替泊芬
《Determination of the migration effect and molecular docking of verteporfin in different subtypes of breast cancer cells》
Yes‑associated protein (YAP), a downstream effector of the Hippo pathway, is overexpressed in human cancers and is associated with proliferation, apoptosis, migration, invasion and resistance to chemotherapy drugs in breast cancer cells. Verteporfin (VP) is used as a photosensitizer in the treatment of neovascular macular degeneration. VP is also identified as an inhibitor of YAP/TEA domain transcription factor (TEAD) interaction in the absence of light activation. However, detailed structural information about VP and YAP interactions is relatively scarce and VP research targeting YAP in different molecular subtypes of breast cancer cells is also rare. The aims of the present study were to structurally describe the VP binding site in the YAP crystal structure and to verify the non‑photoreactive VP effect targeting YAP on the migration of different molecular subtypes of breast cancer cells. The crystal structure of VP and YAP was calculated by AutoDock 4.2 and the result was illustrated using PyMOL. The non‑photoactivated VP effect on the migration of Luminal A MCF‑7, Luminal B BT‑474 and triple‑negative breast cancer BT‑549 breast cancer cells was evaluated by wound healing and Transwell migration experiments. Results from molecular docking experiments demonstrated that VP could interact through hydrogen bonds and hydrophobic interactions with important YAP residues involved in TEADs binding (Gln82, Val84, Met86 and Arg89). Migration experiments revealed that the non‑photoinduced VP could inhibit the migration of different molecular subtypes of breast cancer cells. The results of the present study indicated that VP may be a novel repositioned drug for breast cancer treatment in the future.
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二、帕唑帕尼、达沙替尼、他汀类
5 s% M1 k9 R$ ^$ Z《Small molecules inhibiting the nuclear localization of YAP/TAZ for chemotherapeutics and chemosensitizers against breast cancers》
# |( P) Y( T1 [& DWe screened about 400 chemicals with known targets from SCADS inhibitor kit (provided by the Screening Committee of Anticancer Drugs, Japan) which consists of classical anti-cancer agents, kinase inhibitors, metabolic pathway inhibitors, and signaling pathway inhibitors, including FDA-approved drugs [20]. MDA-MB-231 cells were treated with chemicals and nuclear localization of YAP was evaluated by immunofluorescence. Chemicals which induced nuclear exclusion of YAP were treated as positive. We found that thiazovivin, dasatinib, lovastatin, cucurbitacin I, and pazopanib inhibited the nuclear localization of YAP (Fig. 1A). Among them, dasatinib, statins, and pazopanib are approved as clinically used drugs, and we therefore analyzed them further. We found that dasatinib, fluvastatin, and pazopanib inhibited nuclear localization of YAP and TAZ in the nanomolar to micromolar range, although the effect of pazopanib on the nuclear localization of YAP/TAZ was relatively weak compared to the other two drugs (Fig. 1B). They also inhibited the YAP/TAZ-TEAD-dependent reporter activity (Fig. 1C). We found that they also reduced the transcripts of CTGF, whose transcription is dependent on YAP/TAZ (Fig. 1D). Dasatinib and fluvastatin are known to change actin dynamics, and this leads to phosphorylation of YAP/TAZ [19]. Dasatinib inhibits SRC and affects YAP nuclear localization [21]. Statins inhibit HMG-CoA reductase and lead to impaired geranylgeranylation of RHOA, resulting in the inactivation of YAP/TAZ as reported recently [22,23]. We reproduced the geranylgeranylation-dependent inactivation of YAP/TAZ by fluvastatin, as the simultaneous addition of geranylgeranyl diphosphate (GGPP), but not farnesyl diphosphate (FPP), with fluvastatin canceled the effect of fluvastatin (Supplementary Fig. S1). We also found that the direct inhibition of protein geranylgeranylation recapitulated phosphorylation of YAP (Supplementary Fig. S1). These results confirmed the RHOA-dependent inactivation of YAP/TAZ by statins [22,23].
Pazopanib inhibits VEGFR and PDGFR signaling. VEGF signaling induces activation of RHOA in cervical cancer cells as well as vascular endothelial cells [24,25]. Inhibition of VEGF signaling is known to impair the activation of SRC and FAK, leading to impaired activation of RHOA. PDGF signaling also induced activation of RHOA [26]. MDA-MB-231 is known to express VEGFR2, a VEGFR family member [27] and PDGFR [28]. We hypothesized that the phosphorylation of YAP/TAZ accounted for the inhibition of YAP/TAZ nuclear localization by pazopanib. Therefore, we examined whether pazopanib induced the phosphorylation of YAP and TAZ, and found the increase in the ratio of phosphorylated YAP and TAZ by this drug by pazopanib similar to that by dasatinib and fluvastatin (Fig. 1E i), suggesting that pazopanib also induces YAP/TAZ phosphorylation. We further noted that treatment of cells with pazopanib reduced the total amount of YAP/TAZ in the cell. This reduction was canceled by a proteasome inhibitor, MG-132, (Fig. 1E ii) suggesting that pazopanib facilitates degradation of YAP/TAZ by the ubiquitin–proteasome system as previously described [29].
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三、氯丙嗪
8 s0 P7 j( H5 \9 i《氯丙嗪对膀胱癌BT-B细胞迁移功能的影响》
“与对照组相比，氯丙嗪作用于BT-B细胞后，YAP1(t=6.12,P<0.05;t=7.64,P<0.05)和RAP1A(t=4.87,P<0.05;t=8.30,P<0.05)的蛋白表达水平和mRNA表达水平（t=21.13,P<0.001;t=40.59,P<0.001）均显著降低；与对照组相比，氯丙嗪给药处理2 h后YAP1的荧光表达明显变弱”

四、双氢青蒿素
) {3 k, m# e  R) r% c5 x8 h1、《Dihydroartemisinin inhibited interleukin-18 expression by decreasing YAP1 in hepatocellular carcinoma cells》
. f5 w2 }/ _0 Z" C6 r2、《Dihydroartemisinin promoted FXR expression independent of YAP1 in hepatocellular carcinoma》
3、《Dihydroartemisinin inhibited the Warburg effect through YAP1/SLC2A1 pathway in hepatocellular carcinoma》
$ N/ |1 W8 `1 G5 y: Z& M4、《Dihydroartemisinin broke the tumor immunosuppressive microenvironment by inhibiting YAP1 expression to enhance anti-PD-1 efficacy》
  B2 f- f, y3 b: C5、《Dihydroartemisinin increased the abundance of Akkermansia muciniphila by YAP1 depression that sensitizes hepatocellular carcinoma to anti-PD-1 immunotherapy》
6、《Dihydroartemisinin reduced lipid droplet deposition by YAP1 to promote the anti-PD-1 effect in hepatocellular carcinoma》
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五、多巴酚丁胺
1、《A cell-based assay to screen stimulators of the Hippo pathway reveals the inhibitory effect of dobutamine on the YAP-dependent gene transcription》
We here developed a cell-based method of screening reagents that induce the recruitment of YAP to the cytosol. Using this method, we found that dobutamine inhibits the YAP-dependent gene transcription. Contrary to our expectations, the effect of dobutamine is independent of the Hippo pathway but our method opens the possibility to discover Hippo pathway stimulators or Hippo-independent YAP inhibitors.
- x4 U8 k% r% W2、《Inhibitory effects of dobutamine on human gastric adenocarcinoma》
The expression of YAP was detected mainly in the nucleus in the absence of dobutamine. However, reduced expression of phosphorylated YAP was mainly found in the cytosol following treatment with dobutamine.

9 Q$ ]3 p; y, i4 e" Y六、去甲斑螯素
4 f9 F; ]$ x, v+ V4 V《Repression of YAP by NCTD disrupts NSCLC progression》
) E$ Y; b" K( _' f7 Y# zwe evaluated the specificity of norcantharidin (NCTD) in repressing YAP to inhibit non-small cell lung carcinoma (NSCLC) progression. Our study revealed that YAP signal pathways were aberrantly activated in lung cancer tissues and cells which rendered more proliferative and invasive phenotypes to human lung cancer cells. We confirmed that NCTD specifically repressed YAP signaling pathway to interfere the YAP-mediated non-small cell lung carcinoma progression and metastasis via arresting cell cycle, enhancing apoptosis and inducing senescence. We also found NCTD-mediated repression of YAP decreased epithelial-to-mesenchymal transition (EMT) and reduced the motile and invasive cellular phenotype in vitro via enhancing E-cadherin and decreasing fibronectin/vimentin. Mechanistic investigations revealed that NCTD transcriptionally downregulated YAP and post-translationally modulated the subcellular redistribution of YAP between nucleus and cytoplasm. Collectively, our results indicated that NCTD is a novel therapeutic drug candidate for NSCLC which specifically and sensitively target YAP signal pathway.