Tivantinib (ARQ 197)是一種口服、非三磷酸腺苷競(jìng)爭(zhēng)性、選擇性、小分子met原癌基因(c-MET)抑制劑。計(jì)算出的tivantinib抑制重組人c-MET的抑制常數(shù)(Ki)約為355 nmol/L c-MET是一種受體酪氨酸激酶，是肝細(xì)胞生長(zhǎng)因子(HGF)的高親和力受體。HGF/c-MET信號(hào)通路失調(diào)經(jīng)常發(fā)生在人類癌癥中[1]。

     Tivantinib對(duì)VEGF受體-3 (Flt4)、p21活化激酶3、鈣調(diào)素依賴性激酶ⅱδ和Pim-1有微弱的抑制作用[1]。Tivantinib對(duì)多種人類腫瘤細(xì)胞系表現(xiàn)出細(xì)胞毒性活性，EC50范圍為300-600 nmol/L [4]。值得注意的是，A549、H3122、PC9 (Del E746_A750)、PC9 GR4 (Del E746_A750/T790M)、HCC827、HCC827 GR6、H1993和EBC-1細(xì)胞系顯示出對(duì)替伐替尼一定程度的敏感性，IC50s在0.36和0.8微米之間[5]。在腫瘤細(xì)胞系中，GTL-16、MKN-45、Hs746T、SNU-5、EBC-1、H1993、NCI-H441、A549、HCT-116、U87-MG、A2780和TOV-112D，tivantinib不依賴于c-MET基因擴(kuò)增和MET蛋白表達(dá)而無差別地抑制細(xì)胞增殖，EC50范圍為60至600 nmol/L。進(jìn)一步的研究表明，tivantinib促進(jìn)有絲分裂停滯，防止細(xì)胞重新進(jìn)入G1，并驅(qū)動(dòng)。

     Tivantinib已在多種人類腫瘤細(xì)胞系和人類肺癌、結(jié)腸癌、前列腺癌、胰腺癌和乳腺癌的異種移植模型中顯示出抗腫瘤活性[1] [2] [3]。雌性4周齡無胸腺裸(nu/nu)小鼠用作實(shí)驗(yàn)動(dòng)物。從細(xì)胞注射后14至21天開始，與對(duì)照組相比，120 mg/kg劑量的Tivantinib顯著抑制了治療動(dòng)物骨中的腫瘤負(fù)荷。增加tivantinib的劑量可減少溶骨性病變的數(shù)量和范圍[6]。

產(chǎn)品性質(zhì)：

Cas No.:905854-02-6

別名:(3R,4R)-3-(5,6-二氫-4H-吡咯并[3,2,1-IJ]喹啉-1-基)-4-(1H-吲哚-3-基)吡咯烷-2,5-二酮,ARQ-197;ARQ197

化學(xué)名: (3S,4R)-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione

Canonical SMILES:O=C([C@H](C(C1=CC=C2)=CN3C1=C2CCC3)[C@@H]4C5=CNC6=CC=CC=C56)NC4=O

分子式:C23H19N3O2

分子量:369.42

溶解度:≥ 18.471mg/mL in DMSO

儲(chǔ)存條件:Store at -20°C

注意事項(xiàng)：

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References:

[1].  Ryohei Katayama, Aki Aoyama, Takao Yamori, et al. Cytotoxic Activity of Tivantinib (ARQ 197) Is Not Due Solely to c-MET Inhibition. Cancer Research, 2013, 73(10): 3087-3097.

[2].  Andrew J.Wagner, John M. Goldberg, Steven G. DuBois, et al. Tivantinib (ARQ 197), a Selective Inhibitor of MET, in Patients with Microphthalmia Transcription Factor–Associated Tumors. Cancer, 2012: 5894-5902.

[3].  N. Yamamoto, H. Murakami, T. Nishina, et al. The effect of CYP2C19 polymorphism on the safety, tolerability, and pharmacokinetics of tivantinib (ARQ 197): results from a phase I trial in advanced solid tumors. Annals of Oncology, 2013, 00: 1–7.

[4].  Cristina Basilico, Selma Pennacchietti, Elisa Vigna, et al. Tivantinib (ARQ197) Displays Cytotoxic Activity That Is Independent of Its Ability to Bind MET. Clin Cancer Res, 2013, 19(9):2381-92.

[5].  Cristina Basilico, Selma Pennacchietti, Elisa Vigna, et al. Tivantinib (ARQ197) Displays Cytotoxic Activity That Is Independent of Its Ability to Bind MET. Clinical Cancer Research, 2013, 19(9): 2381–92.

[6].  Sara Previdi, Giovanni Abbadessa, Francesca Dalò, et al. Breast Cancer–Derived Bone Metastasis Can Be Effectively Reduced through Specific c-MET Inhibitor Tivantinib (ARQ 197) and shRNA c-MET Knockdown. Mol Cancer Ther, 2011, 11(1):214-23.