Futibatinib (TAS-120)   中文名称: 福巴替尼

FGFR1 (IC50 = 3.9 nM); FGFR2 (IC50 = 1.3 nM); FGFR3 (IC50 = 1.6 nM); FGFR4 (IC50 = 8.3 nM); wild-type FGFR2 (IC50 = 0.3 nM); FGFR2 V5651 (IC50 = 1-3 nM); FGFR2 N550H (IC50 = 3.6 nM); FGFR2 E566G (IC50 = 2.4 nM)

Futibatinib (TAS-120) 是一种永久性成纤维细胞生长因子受体 (FGFR) 抑制剂，可抑制所有四种 FGFR 亚型，FGFR1、FGFR2、FGFR3 和 FGFR4 的酶半衰期 (IC50) 分别为 1.8 nM、1.4 nM、1.6 nM 、 和 3.7 nM，分别。

TAS-120（3、30、100 mg/kg/天，口服）在小鼠中发挥抗肿瘤作用。 TAS-120通过中等间隔给药，如隔日给药、每周2次间歇给药，降低持续升高和体重抑制的血磷水平，表现出抗肿瘤效果，每日给药有效抗肿瘤。 [1]。

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为了在体内证实这些结果，我们筛选了一组患者来源的ICC异种移植物（PDX）模型，以检测FGFR的改变，并确定了一个携带FGFR2-KIAA1217融合的模型（命名为MG69）（补充图S1G）。用Futibatinib（TAS-120）治疗MG69 PDX肿瘤（从体积达到~500 mm3时开始）导致肿瘤消退和完全增殖停滞，在三天内效果明显，并持续14天（图2E，F）。此外，在MG69 PDX肿瘤中，FGFR抑制抑制了MEK/ERK和SHP2活性，但没有抑制PI3K信号传导（图2G）。因此，FGFR激活的ICC模型高度依赖FGFR活性来维持生长，并在体外和体内维持MEK/ERK信号传导[1]。

1-[（3S）-3-[4-氨基-3-[2-（3,5-二甲氧基苯基）乙炔基]-1H-吡唑并[3,4-d]嘧啶-1-基]-1-吡咯烷基]-2-丙烯-1-酮（TAS-120）是成纤维细胞生长因子受体（FGFR）家族的不可逆抑制剂，目前正在对确诊的晚期转移性实体瘤患者进行I/II期临床试验。这种抑制剂特异性靶向FGFR酪氨酸激酶结构域的P环，与蛋白质的半胱氨酸侧链形成共价加合物。我们的质谱实验表征了共价复合物形成过程中异常快速的化学反应。这种反应性的结构基础由三种X射线晶体结构的序列揭示：自由配体结构、可逆FGFR1结构和首次报道的不可逆FGFR1加合物结构。我们假设TAS-120最显著的反应性特征是其固有的对FGFR P-环进行构象采样的能力。在设计新型共价FGFR抑制剂时，这种现象提出了一种有吸引力的策略，需要与TAS-120类似地适当定位丙烯酰胺基团[2]。

FGFR 过表达人胃癌细胞系 OCUM-2MD3 细胞（在培养基 (DMEM) 中含有 10% 胎牛血清 (FBS) 的 Dulbecco's Modified Eagle）常规传代，细胞密度不超过 80%。为了开始细胞抑制活性的测试，将OCUM-2MD3细胞悬浮于上述DMEM培养基中，将每孔细胞数接种到96孔平底板的每孔中后培养3000个。一天，在含有 5% 二氧化碳气体的培养箱中于 37°C 下进行。第二天，将其在DMSO中阶段稀释至测试化合物终浓度的100倍。用DMSO溶液稀释的培养基进行试验化合物的培养，在含有0.5%细胞的培养板的每个孔中添加DMSO终浓度，在含有5%二氧化碳气体的培养箱中培养72 37°C 小时。使用细胞计数试剂盒-8，按照Dojindo Laboratories推荐的方案进行添加测试化合物的培养时间和72小时后的细胞数的测量。添加各板中含有的试剂盒，在含有5％二氧化碳的培养箱中于37℃下进行预定时间的显色反应。反应完成后，使用酶标仪在450 nm波长处测量吸光度。由下式计算生长抑制率，求出抑制50％时的试验化合物的浓度(GI50(nM))。

The old 6-week-old male nude rats with an intermittent administration schedule are transplanted to the right chest of the anti-tumor effect human gastric cancer strain (OCUM-2MD3). Measuring the tumor's volume after implantation and its major and minor axes in millimeters: The day 0 of the days that are conducted in groups of (n=5) is determined by allocating the mouse average TV to each group after the tumor volume TV has been calculated. Futibatinib (TAS-120)  is prepared so that it contains 3 mg/kg/day and 30 mg/kg/day. 3 mg/kg/day is taken orally every day, while 30 mg/kg/day is taken orally every other day. 100 mg/kg/day is taken orally twice a week starting on day 1, with a 14-day evaluation period and a 15-day final valuation date.

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PDX treatment studies [1]
To develop an FGFR2 fusion human PDX, we obtained tissue from a fresh resection specimen from a patient with an FGFR2-KIAA1217 fusion ICC tumor, per our IRB-approved protocol. The tissue was rinsed in HBSS and cut into 0.3–0.5 mm3 pieces with sterile razor blades. These tumor pieces were implanted subcutaneously into 6–8-week old female NSG mice. Tumor size was measured with a digital caliper. Upon reaching ~500 mm3, mice were randomized to either vehicle control or 25 mg/kg Futibatinib (TAS-120) (in hydroxypropyl methyl cellulose solution) by oral gavage daily for three and fourteen days prior to harvest.

Absorption, Distribution and Excretion
Tmax ranges from 1.2 to 22.8 hours, with a median value of two hours. In healthy subjects, a high-fat and high-calorie meal (900 to 1000 calories with approximately 50% of total caloric content from fat) decreased futibatinib AUC by 11% and Cmax by 42%.
Following a single oral dose of 20 mg radiolabeled futibatinib, approximately 91% of the total recovered radioactivity was observed in feces and 9% in urine, with negligible unchanged futibatinib in urine or feces.
The geometric mean (CV%) apparent volume of distribution (Vc/F) is 66 L (18%).
The geometric mean (CV%) apparent clearance (CL/F) is 20 L/h (23%).

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Metabolism / Metabolites
_In vitro_, futibatinib is primarily metabolized by CYP3A and to a lesser extent by CYP2C9 and CYP2D6. Unchanged futibatinib is the major drug-related moiety in plasma (accounting for 59% of radioactivity) in healthy subjects.

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Biological Half-Life
The mean (CV%) elimination half-life (t_1/2) of futibatinib is 2.9 hours (27%).

Hepatotoxicity
In the open label clinical trials of futibatinib, adverse events were common and led to dose interruptions in 66%, dose reductions in 58%, and drug discontinuation in 5% of patients but only a small proportion of these were due to serum aminotransferase elevations. In preregistration trials in 103 patients with cholangiocarcinoma, ALT elevations arose in 50% and to above 5 times ULN in 7%. The elevations were typically self-limited and resolved rapidly with or without dose adjustments. No patients developed clinically apparent liver injury or jaundice. Publications on the efficacy and safety of futibatinib rarely mentioned serum ALT elevations or hepatotoxicity. Since its approval, there have been no reports clinically apparent liver injury attributed to futibatinib. However, the total clinical experience with its use has been limited and the frequency of serum aminotransferase elevations during therapy suggest that clinically significant liver injury may occur.
Likelihood score: E* (unproven, but possible rare cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the clinical use of futibatinib during breastfeeding. Because futibatinib is 95% bound to plasma proteins, the amount in milk is likely to be low. The manufacturer recommends that breastfeeding be discontinued during futibatinib therapy and for 1 week after the last dose.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Futibatinib is 95% bound to human plasma protein at 0.2 to 5 µmol/L _in vitro_, primarily to albumin and α1-acid glycoprotein.

[1]. 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.

[2]. 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.

[3]. Molecular targeted therapies: Ready for "prime time" in biliary tract cancer [published online ahead of print, 2020 Mar 12]. J Hepatol. 2020;S0168-8278(20)30165-3.

Pharmacodynamics
Futibatinib is an anticancer agent with demonstrated anti-tumour activity in mouse and rat xenograft models of human tumours with activating FGFR genetic alterations. Futibatinib is not expected to affect cell lines with no FGFR genomic aberrations. It suppresses the growth of tumours in a dose-dependent manner.

C22H22N6O3

418.4485

418.18

C, 63.15; H, 5.30; N, 20.08; O, 11.47

1448169-71-8

71621331

Off-white to light beige solid powder

1.0±0.1 g/cm3

244.0±0.0 °C at 760 mmHg

87.5±21.3 °C

0.0±0.4 mmHg at 25°C

1.490

2.39

108

1

7

6

31

723

1

O=C(C=C)N1CC[C@@H](C1)N1C2C(=C(N)N=CN=2)C(C#CC2C=C(C=C(C=2)OC)OC)=N1

KEIPNCCJPRMIAX-HNNXBMFYSA-N

InChI=1S/C22H22N6O3/c1-4-19(29)27-8-7-15(12-27)28-22-20(21(23)24-13-25-22)18(26-28)6-5-14-9-16(30-2)11-17(10-14)31-3/h4,9-11,13,15H,1,7-8,12H2,2-3H3,(H2,23,24,25)/t15-/m0/s1

1-[(3S)-3-[4-amino-3-[2-(3,5-dimethoxyphenyl)ethynyl]pyrazolo[3,4-d]pyrimidin-1-yl]pyrrolidin-1-yl]prop-2-en-1-one

Futibatinib; TAS-120; TAS 120; 1448169-71-8; Lytgobi; UNII-4B93MGE4AL; 4B93MGE4AL; Futibatinib [USAN]; TAS120

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: ≥ 29 mg/mL (~69.3 mM)

配方 1 中的溶解度: 2.08 mg/mL (4.97 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 悬浮液；超声助溶。
例如，若需制备1 mL的工作液，可将100 μL 20.8 mg/mL澄清DMSO储备液加入400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: 2.08 mg/mL (4.97 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 悬浊液; 超声助溶。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.08 mg/mL (4.97 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。