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Purity: ≥98%
Infigratinib (also known as BGJ398; BGJ-398; NVP-BGJ398; Truseltiq) is a novel, potent, selective, and orally bioavailable FGFR (fibroblast growth factor receptors) inhibitor with potential antiangiogenic and antineoplastic activities. In order to treat cholangiocarcinoma, the FDA has approved it as an anti-cancer medication as of May 28, 2021. With an IC50 of 0.9 nM/1.4 nM/1 nM in cell-free assays, infigratinib inhibits FGFR1/2/3. FGFR is the target of over 40-fold selectivity when compared to FGFR4, VEGFR2, and Abl, Fyn, Kit, Lck, Lyn, and Yes are the targets of minimal activity. An orthotopic xenograft bladder cancer model in mice demonstrates strong anti-proliferative activity in vitro and strong in vivo antitumor efficacy.
| Targets |
FGFR1 (IC50 = 0.9 nM); FGFR2 (IC50 = 1.4 nM); FGFR3 (IC50 = 1 nM); FGFR4 (IC50 = 60 nM)
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| ln Vitro |
BGJ398 also inhibits VEGFR2 to a lesser extent. BGJ398 has an IC50 of 0.18 μM for inhibiting VEGFR2. Other kinases such as ABL, FYN, KIT, LCK, LYN, and YES are suppressed by BGJ398 with IC50 values of 2.3 μM, 1.9 μM, 0.75 μM, 2.5 μM, 0.3 μM, and 1.1 μM, in that order. BGJ398 impedes the growth of BaF3 cells that are dependent on FGFR1, FGFR2-Q, and FGFR3 at the cellular level, with IC50 values of 2.9 μM, 2.0 μM, and 2 μM, in that order. BGJ398 has an IC50 of 4.6 nM, 4.9 nM, 5 nM, 5 nM, and 168 nM, respectively, and inhibits autophosphorylation on particular tyrosine residues, such as FGFR-WT, FGFR2-WT, FGFR3-K650E, FGFR3-S249C, and FGFR4-WT. Cancer cells that overexpress wild-type (WT) FGFR3, such as RT112, RT4, SW780, and JMSU1, are suppressed by BGJ398 with IC50 values of 5 nM, 30 nM, 32 nM, and 15 nM, respectively.[1]
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| ln Vivo |
BGJ398 inhibits tumor growth and induces stasis in this orthotopic xenograft bladder cancer model after being taken orally for 12 days straight at doses of 10 and 30 mg/kg, respectively. It's interesting to note that the animals that received BGJ398 show either 10% body weight gain (30 mg/kg) or no body weight loss (10 mg/kg), which is another sign of efficacy. One oral dose of BGJ398 monophosphate salt at 4.25 and 8.51 mg/kg is given to female Rowett rats (RT112) that are tumor-bearing. In a dose-dependent manner, BGJ398 dramatically lowers the levels of pFRS2 and pMAPK. In a dose-dependent manner, BGJ398 markedly suppresses bFGF-stimulated angiogenesis. Nevertheless, BGJ398 does not impede the formation of blood vessels induced by VEGF.
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| Enzyme Assay |
The purified GST-fusion FGFR3-K650E kinase domain phosphorylates a synthetic substrate in the presence of radiolabeled ATP to measure the enzymatic kinase activity. The enzyme activity is determined by combining 10 μL of the corresponding substrate mixture (peptidic substrate, ATP, and [γ33P]ATP) with 10 μL of a 3-fold concentrated BGJ398 solution or control. The assay buffer is mixed with 10 μL of a concentrated enzyme solution three times over to start the reactions. The following are the assay components' final concentrations: 0.5 μM ATP (γ-[33P]-ATP 0.1 μCi), 3 mM MnCl2, 3 mM MgCl2, 1 mM DTT, 250 μg/mL PEG 20000, 2 μg/mL poly(EY) 4:1, 1% DMSO, and 10 ng of GST-FGFR3-K650E were added. The assay is performed using the filter binding (FB) method in 96-well plates for 10 minutes at room temperature in a final volume of 30 μL with BGJ398 included. When 20 μL of 125 mM EDTA is added, the enzymatic reactions are stopped, and the amount of 33P incorporated into the polypeptidic substrates is measured as follows: 30 microliters of the halted reaction mixture are placed onto Immobilon-PVDF membranes that have been soaked in methanol for five minutes, rinsed with water, and then soaked in 0.5% H3PO4 for five minutes. The membranes are then mounted on a vacuum manifold that has a disconnected vacuum source. Following spotting, a vacuum is connected, and 200 μL of 0.5% H3PO4 is rinsed through each well. Free membranes are taken out and ished with 1% H3PO4 four times and ethanol once on a shaker. Membranes are dehydrated and covered with a layer of scintillation fluid (10 μL/well). Eventually, a microplate scintillation counter is used to seal and count the plates. The BGJ398 percentage inhibition is analyzed using linear regression to determine the IC50 values.
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| Cell Assay |
The RPMI-1640 medium supplemented with 10% FBS, 4.5 g/L glucose, 1.5 g/L sodium bicarbonate, and Pen/Strep is used to cultivate mouse BaF3 cell lines, whose proliferation and survival have been rendered IL-3-independent by stable transduction with tyrosine kinases activated either by mutation or fusion with a dimerizing partner. Twice a week, cells are passaged. The Luciferase bioluminescent assay is utilized to evaluate the BGJ398-mediated suppression of BaF3 cell proliferation and viability. BaF3 or BaF3 Tel-TK cells that are growing exponentially are seeded into 384-well plates (4250 cells/well) at a volume of 50 μL per well using a μFill liquid dispenser in fresh medium. In a polypropylene 384-well plate, BGJ398 is serially diluted in DMSO. The plates were then incubated at 37 °C (5% CO2) for 48 hours after 50 nL of BGJ398 were added using the pintool transfer device. The luminescence is then measured with an Analyst-GT after adding 25 μL of Bright-Glo. The logarithm of inhibitor concentration is used to generate a logistic fit of the percent cell viability. This is done using custom curve-fitting software. When cell viability is reduced to 50% of a DMSO control, the concentration of BGJ398 is called the IC50 value.
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| Animal Protocol |
Mice: Female HsdNpa: It is done with athymic Nude-nu mice. Over the course of 12 days, infigratinib (BGJ-398) is given orally at doses of 10 and 30 mg/kg/qd in a suspension formulation in PEG300/D5W (2:1, v/v). In order to compare the treatment group to the control group, tumor and body weight data are analyzed using ANOVA and post hoc Dunnett's test. An intragroup comparison is made using the post hoc Tukey test. With GraphPad Prism 4.02, statistical analysis is carried out. The T/C (%) value is computed as a measure of efficacy.
Rats: Female nudity We use 6-to 9-week-old Rowett rats. Using a formulation of infigratinib (BGJ-398), which is a solution in acetic acid-acetate buffer pH 4.6/PEG300 (1:1, v/v), the tumor-bearing rats (n = 8) receive daily gavage treatments of 5, 10, and 15 mg/kg/qd (free base equivalents) for a duration of 20 days. There is a 5 mL/kg application volume. Using calipers, tumor volumes are measured and calculated using the following formula: length×width×height×π/6. T/C (%) is a measure of antitumor activity that is calculated as (mean change in tumor volume of treated animals / mean change in tumor volume of control animals)×100. A regression's percentage is computed. |
| References |
| Molecular Formula |
C26H31CL2N7O3
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|---|---|
| Molecular Weight |
560.48
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| Exact Mass |
559.19
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| Elemental Analysis |
C, 55.72; H, 5.57; Cl, 12.65; N, 17.49; O, 8.56
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| CAS # |
872511-34-7
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| Related CAS # |
Infigratinib phosphate;1310746-10-1
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| Appearance |
White to off-white solid powder
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| SMILES |
CCN1CCN(CC1)C2=CC=C(C=C2)NC3=CC(=NC=N3)N(C)C(=O)NC4=C(C(=CC(=C4Cl)OC)OC)Cl
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| InChi Key |
QADPYRIHXKWUSV-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C26H31Cl2N7O3/c1-5-34-10-12-35(13-11-34)18-8-6-17(7-9-18)31-21-15-22(30-16-29-21)33(2)26(36)32-25-23(27)19(37-3)14-20(38-4)24(25)28/h6-9,14-16H,5,10-13H2,1-4H3,(H,32,36)(H,29,30,31)
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| Chemical Name |
3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-[6-[4-(4-ethylpiperazin-1-yl)anilino]pyrimidin-4-yl]-1-methylurea
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| Synonyms |
NVP-BGJ398; Infigratinib; NVPBGJ398; BGJ398; BGJ-398; NVPBGJ 398; NVPBGJ-398; BG J398
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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) |
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| Solubility (In Vivo) |
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| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7842 mL | 8.9209 mL | 17.8418 mL | |
| 5 mM | 0.3568 mL | 1.7842 mL | 3.5684 mL | |
| 10 mM | 0.1784 mL | 0.8921 mL | 1.7842 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 |
| NCT04233567 | Active Recruiting |
Drug: Infigratinib | Advanced Malignant Solid Neoplasm Cholangiocarcinoma |
Sameek Roychowdhury | January 16, 2020 | Phase 2 |
| NCT04228042 | Active Recruiting |
Drug: Infigratinib Procedure: Surgical Procedure |
Renal Pelvis and Ureter Urothelial Carcinoma |
M.D. Anderson Cancer Center | July 28, 2020 | Phase 1 Phase 2 |
| NCT02657486 | Active Recruiting |
Drug: BGJ398 | Bladder Cancer Non-Muscle-Invasive Urothelial Carcinoma |
Memorial Sloan Kettering Cancer Center |
January 2016 | Not Applicable |
| NCT05019794 | Recruiting | Drug: Infigratinib | Gastric Cancer Solid Tumor |
LianBio LLC | May 13, 2020 | Phase 2 |
| NCT05145010 | Recruiting | Drug: Infigratinib | Achondroplasia | QED Therapeutics, Inc. | December 6, 2021 | Phase 2 |
Targeting Fgfr2-fusion containing tumors with the FGFR-inhibitor BGJ398 results in complete response.Cancer Discov.2018 Mar;8(3):354-369. |
Multiple, different genetic aberrations lead to common elevated MAPK and/or PI3K pathway activation in human breast cancer patients.Cancer Discov.2018 Mar;8(3):354-369. |
Targeting Dhx9-Raf1 and cMet with MEK- and MET-inhibitor, respectively, result in tumor regression or delayed progression.
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