TAS-120
(Synonyms: TAS-120) 目录号 : GC19156
TAS-120是一种口服生物利用度高、选择性强、不可逆的成纤维细胞生长因子受体（FGFR）抑制剂，可降低FGFR1-4的活性（IC₅₀分别为3.9nM、1.3nM、1.6nM和8.3nM）。
Cas No.:1448169-71-8
Sample solution is provided at 25 µL, 10mM.
TAS-120 is a highly bioavailable, selective, and irreversible fibroblast growth factor receptor (FGFR) inhibitor that demonstrates potent inhibitory activity against FGFR1-4, with IC₅₀ values of 3.9nM, 1.3nM, 1.6nM, and 8.3nM[1-2]. TAS-120 covalently binds to a highly conserved cysteine residue in the P-loop of the FGFR ATP-binding pocket, leading to irreversible inhibition, suppression of FGFR-mediated signaling pathways, inhibition of tumor cell proliferation, and promotion of cell death in FGFR-expressing tumor cells[3-4].
In vitro, treatment of MCF10A cells expressing FGFR2-BICC1 fusion, FGFR2 Y375C mutation, or wild-type FGFR2 with TAS-120 (0-100μM) for 4 days, TAS-120 significantly inhibited phosphorylation of FGFR2, ERK1/2, Akt. TAS-120 reduced cell viability (IC₅₀ values of 18nM, 137nM, and 18μM, respectively). In FGFR2 Y375C-mutated PDX.007CL cells, TAS-120 also significantly inhibited cell proliferation (IC₅₀ of 0.48μM)[5]. Treatment of Ba/F3 cells expressing TEL-FGFR4 or RMS559 rhabdomyosarcoma cells harboring the FGFR4 V550L mutation with TAS-120 (0-20μM) for 72 hours, TAS-120 significantly suppressed FGFR4 autophosphorylation and the ERK1/2 signaling pathway, induced apoptosis, and inhibited colony formation[6].
In vivo, in an FGFR2-expressing OCUM-2MD3 gastric cancer xenograft model, oral administration of TAS-120 (0.15, 0.5, 1.5, and 5mg/kg; once daily for 14 days) dose-dependently and significantly inhibited tumor growth, with no signs of early resistance observed during treatment[7]. In an FGFR2-KIAA1217 fusion-positive patient-derived xenograft (PDX) model (MG69), oral treatment with TAS-120 (25mg/kg; once daily) resulted in tumor regression and complete suppression of proliferation, with effects evident within 3 days and sustained for 14 days, accompanied by inhibition of downstream MEK/ERK and SHP2 signaling pathways[8].
References:
[1] Kalyukina M, Yosaatmadja Y, Middleditch MJ, et al. TAS-120 Cancer Target Binding: Defining Reactivity and Revealing the First Fibroblast Growth Factor Receptor 1 (FGFR1) Irreversible Structure. ChemMedChem. 2019 Feb 19;14(4):494-500.
[2] Wu Q, Ellis H, Siravegna G, et al. Landscape of Clinical Resistance Mechanisms to FGFR Inhibitors in FGFR2-Altered Cholangiocarcinoma. Clin Cancer Res. 2024 Jan 5;30(1):198-208.
[3] Goyal L, Meric-Bernstam F, Hollebecque A, et al. Futibatinib for FGFR2-Rearranged Intrahepatic Cholangiocarcinoma. N Engl J Med. 2023 Jan 19;388(3):228-239.
[4] Facchinetti F, Loriot Y, Brayé F, et al. Understanding and Overcoming Resistance to Selective FGFR Inhibitors across FGFR2-Driven Malignancies. Clin Cancer Res. 2024 Nov 1;30(21):4943-4956.
[5] Saridogan T, Akcakanat A, Zhao M, et al. Efficacy of futibatinib, an irreversible fibroblast growth factor receptor inhibitor, in FGFR-altered breast cancer. Sci Rep. 2023 Nov 18;13(1):20223.
[6] Wu JT, Cheuk A, Isanogle K, et al. Preclinical Evaluation of the FGFR-Family Inhibitor Futibatinib for Pediatric Rhabdomyosarcoma. Cancers (Basel). 2023 Aug 9;15(16):4034.
[7] Sootome H, Fujita H, Ito K, et al. Futibatinib Is a Novel Irreversible FGFR 1-4 Inhibitor That Shows Selective Antitumor Activity against FGFR-Deregulated Tumors. Cancer Res. 2020 Nov 15;80(22):4986-4997.
[8] Goyal L, Shi L, Liu LY, et al. TAS-120 Overcomes Resistance to ATP-Competitive FGFR Inhibitors in Patients with FGFR2 Fusion-Positive Intrahepatic Cholangiocarcinoma. Cancer Discov. 2019 Aug;9(8):1064-1079.
TAS-120是一种口服生物利用度高、选择性强、不可逆的成纤维细胞生长因子受体（FGFR）抑制剂，可降低FGFR1-4的活性（IC₅₀分别为3.9nM、1.3nM、1.6nM和8.3nM）[1-2]。TAS-120通过与FGFR的ATP口袋中高度保守的P环半胱氨酸残基共价结合，实现不可逆抑制，从而抑制FGFR介导的信号传导通路和肿瘤细胞增殖，并促进表达FGFR的肿瘤细胞死亡[3-4]。
在体外，TAS-120（0-100μM）处理表达FGFR2-BICC1融合、FGFR2 Y375C突变或FGFR2野生型的MCF10A细胞4天，TAS-120显著抑制FGFR2及ERK1/2和Akt的磷酸化，并降低细胞活力（IC50分别为18nM、137nM和18μM）；在FGFR2 Y375C突变的PDX.007CL细胞中，TAS-120也显著抑制细胞增殖（IC50为0.48μM）[5]。TAS-120（0-20μM）处理表达TEL-FGFR4的Ba/F3细胞或携带FGFR4 V550L突变的RMS559横纹肌肉瘤细胞72小时，TAS-120显著抑制FGFR4自磷酸化及ERK1/2信号通路，并诱导细胞凋亡，同时抑制细胞集落形成[6]。
在体内，在表达FGFR2的OCUM-2MD3胃癌异种移植模型中，口服TAS-120（0.15、0.5、1.5和5mg/kg；每日一次，持续14天）可剂量依赖性地显著抑制肿瘤生长，且治疗期间未出现早期耐药迹象[7]。在FGFR2-KIAA1217融合阳性的人源性异种移植（PDX）模型（MG69）中，口服TAS-120（25mg/kg；每日一次）治疗可导致肿瘤消退和完全增殖抑制，效果在3天内显现并持续14天，同时伴随FGFR下游MEK/ERK和SHP2信号通路的抑制[8]。
| Cell experiment [1]: | |
Cell lines | RMS559 (a fusion-negative rhabdomyosarcoma cell line with an FGFR4V550Lactivating mutation); RH4 and SCMC (fusion-positive rhabdomyosarcoma cell lines with FGFR4 overexpression); Ba/F3 TEL-FGFR4 (an interleukin-3 dependent murine hematopoietic cell line engineered to express a constitutively active TEL-FGFR4 fusion) |
Preparation Method | Cells were cultured in their respective media (e.g., RPMI-1640 or DMEM supplemented with 10% fetal bovine serum) and treated with TAS-120 (0–20μM) for 72 hours. |
Reaction Conditions | 0–20μM; 72 hours |
Applications | TAS-120 potently inhibited FGFR4 phosphorylation and its downstream signaling target ERK1/2 in RMS559 cells in a dose-dependent manner. TAS-120 significantly decreased the viability of RMS559 cells (EC50= 0.48µM), which harbor the activating FGFR4 mutation, and induced apoptosis (Caspase 3/7 activation). In contrast, RH4 and SCMC cell lines without the activating mutation were substantially less sensitive (EC50 values of 6.64µM and 11.7µM, respectively). |
| Animal experiment [2]: | |
Animal models | Athymic nude (nu/nu) mice, severe combined immunodeficient (NOD-SCID) mice, and nude rats bearing human tumor xenografts (including OCUM-2MD3 gastric cancer, KMS-11 multiple myeloma, MFM-223 breast cancer, RT-112/84 bladder cancer, and H1581 lung cancer models) |
Preparation Method | Tumor xenografts were established by subcutaneous implantation of cancer cells mixed with Matrigel. Treatment with TAS-120 (0.15 to 5mg/kg) or vehicle control (0.5% hydroxypropyl methylcellulose) was initiated orally by gavage when tumors reached a predetermined size (>0.2cm³). |
Dosage form | 0.15-5mg/kg; orally; once daily for 14-27 days. |
Applications | Oral administration of TAS-120 led to significant, dose-dependent tumor regression and growth inhibition in various FGFR-driven human tumor xenograft models. Tumor reduction was associated with sustained inhibition of FGFR phosphorylation and its downstream signaling pathways (ERK and Akt), which was proportional to the administered dose. All once-daily dosing regimens were well-tolerated, without inducing body weight reduction in mice. |
References: | |
| Cas No. | 1448169-71-8 | SDF | |
| 别名 | TAS-120 | ||
| Canonical SMILES | O=C(C=C)N(C1)CC[C@@H]1N(N=C2C#CC3=CC(OC)=CC(OC)=C3)C4=C2C(N)=NC=N4 | ||
| 分子式 | C22H22N6O3 | 分子量 | 418.45 |
| 溶解度 | DMSO : ≥ 29 mg/mL (69.30 mM) | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.3898 mL | 11.9489 mL | 23.8977 mL |
| 5 mM | 478 μL | 2.3898 mL | 4.7795 mL |
| 10 mM | 239 μL | 1.1949 mL | 2.3898 mL |
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