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Purity: ≥98%
Futibatinib (formerly also known as TAS 120; TAS-120) is a novel, potent, irreversible and orally bioavailable inhibitor of the fibroblast growth factor receptor (FGFR) with potential anticancer activity. Its IC50 values for inhibiting FGFR 1-4 are 3.9, 1.3, 1.6, and 8.3 nM, in that order. TAS-120 specifically and irreversibly binds to FGFR, inhibiting it. This may lead to increased cell death in tumor cells overexpressing FGFR, as well as the inhibition of the FGFR-mediated signal transduction pathway and tumor cell proliferation. Many different types of tumor cells express FGFR, a receptor tyrosine kinase that is critical to the growth, differentiation, and survival of tumor cells. 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.
| Targets |
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)
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| ln Vitro |
Futibatinib (TAS-120) is a permanent fibroblast growth factor receptor (FGFR) inhibitor that inhibits all four FGFR subtypes, with enzyme half-lives (IC50) for FGFR1, FGFR2, FGFR3, and FGFR4 being 1.8 nM, 1.4 nM, 1.6 nM, and 3.7 nM, respectively.
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| ln Vivo |
TAS-120 (3, 30, 100 mg/kg/day, p.o.) exerts an anti-tumor effect in mice. By lowering the blood phosphorus level's sustained elevation and weight suppression, as well as by intermittently administering the drug every other day and twice a week, TAS-120 exhibits anti-tumor effects. Its daily administration is also effective.
To corroborate these results in vivo, we screened a collection of patient-derived xenograft (PDX) models of ICC for FGFR alterations, and identified a model harboring a FGFR2-KIAA1217 fusion (designated MG69) (Supplemental Figure S1G). Treatment of MG69 PDX tumors with Futibatinib (TAS-120) (starting when the volume reached ~500 mm3) led to tumor regression and complete proliferative arrest, with prominent effects evident within three days and persisting over a 14-day course (Figure 2E, F). Moreover, FGFR inhibition suppressed MEK/ERK and SHP2 activity, but not PI3K signaling, in MG69 PDX tumors (Figure 2G). Thus, FGFR activated ICC models are highly dependent on FGFR activity to sustain growth and maintain MEK/ERK signaling in vitro and in vivo [1]. |
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| Enzyme Assay |
1-[(3S)-3-[4-Amino-3-[2-(3,5-dimethoxyphenyl)ethynyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-pyrrolidinyl]-2-propen-1-one (TAS-120) is an irreversible inhibitor of the fibroblast growth factor receptor (FGFR) family, and is currently under phase I/II clinical trials in patients with confirmed advanced metastatic solid tumours harbouring FGFR aberrations. This inhibitor specifically targets the P-loop of the FGFR tyrosine kinase domain, forming a covalent adduct with a cysteine side chain of the protein. Our mass spectrometry experiments characterise an exceptionally fast chemical reaction in forming the covalent complex. The structural basis of this reactivity is revealed by a sequence of three X-ray crystal structures: a free ligand structure, a reversible FGFR1 structure, and the first reported irreversible FGFR1 adduct structure. We hypothesise that the most significant reactivity feature of TAS-120 is its inherent ability to undertake conformational sampling of the FGFR P-loop. In designing novel covalent FGFR inhibitors, such a phenomenon presents an attractive strategy requiring appropriate positioning of an acrylamide group similarly to that of TAS-120 [2].
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| Cell Assay |
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| Animal Protocol |
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.
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. |
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| ADME/Pharmacokinetics |
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%). 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. Biological Half-Life The mean (CV%) elimination half-life (t1/2) of futibatinib is 2.9 hours (27%). |
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| Toxicity/Toxicokinetics |
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). 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. 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. |
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| References |
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| Additional Infomation |
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. |
| Molecular Formula |
C22H22N6O3
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|---|---|
| Molecular Weight |
418.4485
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| Exact Mass |
418.18
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| Elemental Analysis |
C, 63.15; H, 5.30; N, 20.08; O, 11.47
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| CAS # |
1448169-71-8
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| PubChem CID |
71621331
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| Appearance |
Off-white to light beige solid powder
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| Density |
1.0±0.1 g/cm3
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| Boiling Point |
244.0±0.0 °C at 760 mmHg
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| Flash Point |
87.5±21.3 °C
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| Vapour Pressure |
0.0±0.4 mmHg at 25°C
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| Index of Refraction |
1.490
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| LogP |
2.39
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
31
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| Complexity |
723
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| Defined Atom Stereocenter Count |
1
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| SMILES |
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
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| InChi Key |
KEIPNCCJPRMIAX-HNNXBMFYSA-N
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| InChi Code |
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
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| Chemical Name |
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
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| Synonyms |
Futibatinib; TAS-120; TAS 120; 1448169-71-8; Lytgobi; UNII-4B93MGE4AL; 4B93MGE4AL; Futibatinib [USAN]; TAS120
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO: ≥ 29 mg/mL (~69.3 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.08 mg/mL (4.97 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 2.08 mg/mL (4.97 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (4.97 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3898 mL | 11.9489 mL | 23.8977 mL | |
| 5 mM | 0.4780 mL | 2.3898 mL | 4.7795 mL | |
| 10 mM | 0.2390 mL | 1.1949 mL | 2.3898 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT04189445 | Active Recruiting |
Drug: Futibatinib | Advanced or Metastatic Solid Tumor Myeloid or Lymphoid Neoplasms (MLN) |
Taiho Oncology, Inc. | August 24, 2020 | Phase 2 |
| NCT04093362 | Active Recruiting |
Drug: TAS-120 Drug: Cisplatin/Gemcitabine |
Advanced Cholangiocarcinoma FGFR2 Gene Rearrangements |
Taiho Oncology, Inc. | March 1, 2020 | Phase 3 |
| NCT04024436 | Active Recruiting |
Drug: Futibatinib Drug: Futibatinib plus Fulvestrant |
Metastatic Breast Cancer FGFR 1 High Amplification Metastatic Melanoma |
Taiho Oncology, Inc. | August 30, 2019 | Phase 2 |
| NCT02052778 | Active Recruiting |
Drug: Futibatinib | Urothelial Cancer Primary CNS Tumors |
Taiho Oncology, Inc. | July 2014 | Phase 1 Phase 2 |
| NCT05615818 | Not yet recruiting | Drug: Futibatinib Drug: Ivosidenib |
Biliary Tract Neoplasms | UNICANCER | January 2024 | Phase 3 |
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