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Purity: =98.61%
BLU9931 (BLU-9931; BLU 9931) is an irreversible and selective FGFR4 inhibitor with potential anticancer activity. In a cell-free assay, it inhibits FGFR4 with an IC50 of 3 nM. Compared to other FGFR family kinases like FGFR1/2/3, BLU9931 exhibits high selectivity for inhibiting FGFR4 (297-, 184-, and 50-fold selectivity, respectively). In mice with an overexpressed FGF19 xenograft in the form of an HCC tumor and a liver tumor xenograft model, BLU9931 demonstrates impressive antitumor activity.
| Targets |
FGFR1 (IC50 = 591 nM); FGFR2 (IC50 = 493 nM); FGFR3 (IC50 = 150 nM); FGFR4 (IC50 = 3 nM)
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| ln Vitro |
BLU9931 significantly suppresses the phosphorylation of the FGFR4 signaling pathway in MDA-MB-453 cells. With an EC50 of less than 1 μM, BLU9931 suppresses the growth of HCC cell lines that express an intact FGFR4 signaling complex, including Hep 3B, HUH-7, and JHH-7 cell lines. Additionally, BLU9931 prevents the growth of PDX-derived cell lines that still have functional FGFR4 signaling.[1]
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| ln Vivo |
BLU9931 (300 mg/kg, p.o.) inhibits weight loss caused by tumors and causes tumor regression in mice with FGF19-amplified Hep 3B liver tumors. Tumor regression is also observed in mice treated with BLU9931 (300 mg/kg, p.o.) that bear the FGF19-overexpressing PDX-derived LIXC012 xenografts.[1]
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| Enzyme Assay |
FGFR1–4 Biochemical Assays[1]
In assays for FGFR kinase inhibition, ATP is used at KM. Picomolar to low nanomolar concentrations of FGFR proteins are incubated for 90 minutes at 25°C in 1× Kinase Reaction Buffer (KRB) with 1 μM of CSKtide and 50 to 250 μM ATP, either in the presence or absence of a dosed concentration series of inhibitor. The addition of Stop buffer ends each reaction, and plates are read using a Caliper EZReader2. A four-parameter log[Inhibitor] against response model with floating Hill Slope is used to fit IC50 values. Kinase Selectivity Profiling[1] BLU9931 and BGJ398 were screened at a single concentration of 3 μmol/L and LY-2874455 was screened at a single concentration of 1 μmol/L using the KINOMEscan Assay Platform. Kinetics of Inhibition Assays for KI, kinact, and kinact/KI Estimation[1] On-mechanism inhibition constants were collected using the Omnia assay technology, where 22 dose inhibitor titrations were added to a 384-well Nonbinding surface (NBS™) assay plate containing a substrate mixture of 10 μmol/L Y10-sox peptide and 1 mmol/L ATP prepared in 1× KRB. Reactions were initiated with the addition of recombinant FGFR4 protein and fluorescence intensity readings were collected (λex 360 nm/λem 485 nm) every 74 seconds at room temperature. At the conclusion of each assay, raw fluorescence intensity data representing steady-state kinase activity progress curves were fit for kobs using the model for a first-order exponential. kobs versus inhibitor dose curves were then fit for KI and kinact using a model for irreversible inhibition with autoinactivation. GraphPad Prism was used for all curve fitting. |
| Cell Assay |
Established and PDX-derived HCC cell lines are seeded in 96-well plates with the appropriate growth media, given an overnight attachment period, and then subjected to two cell-doubling cycles of treatment with a dilution series of test compounds. CellTiter-Glo is used to assess cell viability; the results are expressed as background-subtracted relative light units normalized to a control that received DMSO treatment. At 50% inhibition, the relative EC50 values are calculated between the top and bottom plateaus of the dose-response curve.
Proliferation Studies[1] Established and PDX-derived HCC cell lines were seeded in 96-well plates in respective growth media, allowed to attach overnight, and treated with a dilution series of test compounds for two cell-doubling times. Cell viability was determined by CellTiter-Glo, and results represented as background-subtracted relative light units normalized to a DMSO-treated control. Relative EC50 values were determined at 50% inhibition between the top and bottom plateau of the dose–response curve. Detection of Activated Caspase-3/7[1] Hep 3B cells were seeded overnight at 2.5 × 104 cells in white 96-well plates in media containing 5% FBS, then treated for 24 hours at indicated compound concentrations, and processed according to the manufacturer's instructions using the Caspase-3/7 Glo assay. Data are expressed relative to DMSO control-treated cells. FGFR4 Turnover Studies[1] Cells were plated at 4 × 105 cells per well of a 6-well plate in media containing 10% serum and allowed to adhere overnight. Cells were treated with 10 μg/mL cycloheximide for indicated times. Samples were subjected to gel electrophoresis followed by immunoblotting as described above. |
| Animal Protocol |
Mice bearing LIXC012 tumors
~300 mg/kg p.o. In Vivo Studies[1] BLU9931 was formulated in 0.5% carboxymethylcellulose/1% Tween 80 and dosed orally as a suspension twice daily. Sorafenib was dissolved in Cremaphor:EtOH (1:1) and diluted with saline or water to yield the stock solution. Sorafenib was dosed orally once daily. All compound doses are expressed as mg/kg free base. For PK–PD studies, 3 mice were included in each treatment group. Mice received four doses of compound or vehicle. Blood and tumors were collected 8, 12, 20, and 24 hours following the last dose. The concentration of BLU9931 in plasma was determined by LC/MS-MS. A section of each tumor was immediately frozen in liquid nitrogen and stored at −80°C. |
| References | |
| Additional Infomation |
FGFR4 Inhibitor BLU 9931 is an orally bioavailable, selective inhibitor of human fibroblast growth factor receptor 4 (FGFR4), with potential antineoplastic activity. Upon oral administration, FGFR4 antagonist BLU 9931 specifically and irreversibly binds to the cysteine residue at position 552 (Cys 552) that is within the active site of FGFR4. This blocks FGFR4 autophosphorylation and activation of receptor tyrosine kinase activity that would normally occur after binding to its ligand, fibroblast growth factor 19 (FGF19), which both inhibits FGFR4-mediated signaling and leads to an inhibition of tumor cell proliferation in FGF19- and FGFR4-overexpressing cells. FGFR4, a receptor tyrosine kinase, is involved in angiogenesis and in the proliferation, differentiation, and survival of tumor cells. FGFR4 expression is associated with poor prognosis. FGF19 is overexpressed by certain tumor cell types.
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| Molecular Formula |
C26H22CL2N4O3
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| Molecular Weight |
509.38
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| Exact Mass |
508.106
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| Elemental Analysis |
C, 61.31; H, 4.35; Cl, 13.92; N, 11.00; O, 9.42
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| CAS # |
1538604-68-0
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| Related CAS # |
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| PubChem CID |
72710839
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| Appearance |
Off-white to light yellow solid powder
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| Density |
1.4±0.1 g/cm3
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| Index of Refraction |
1.677
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| LogP |
5.13
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
35
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| Complexity |
715
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| Defined Atom Stereocenter Count |
0
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| SMILES |
ClC1C(=C([H])C(=C(C=1C1C([H])=C([H])C2C(=C([H])N=C(N=2)N([H])C2C(=C([H])C([H])=C([H])C=2C([H])([H])[H])N([H])C(C([H])=C([H])[H])=O)C=1[H])Cl)OC([H])([H])[H])OC([H])([H])[H]
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| InChi Key |
TXEBNKKOLVBTFK-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C26H22Cl2N4O3/c1-5-21(33)30-18-8-6-7-14(2)25(18)32-26-29-13-16-11-15(9-10-17(16)31-26)22-23(27)19(34-3)12-20(35-4)24(22)28/h5-13H,1H2,2-4H3,(H,30,33)(H,29,31,32)
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| Chemical Name |
N-[2-[[6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl]amino]-3-methylphenyl]prop-2-enamide
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| Synonyms |
BLU9931; BLU 9931; N-(2-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)-3-methylphenyl)acrylamide; N-[2-[[6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl]amino]-3-methylphenyl]prop-2-enamide; UNII-FQK825B5DX; FQK825B5DX; BLU-9931
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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 |
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| 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) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.08 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
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 (4.08 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. 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 (4.08 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 0.5% carboxymethylcellulose+1% Tween 80 as a suspension: 30mg/mL |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9632 mL | 9.8159 mL | 19.6317 mL | |
| 5 mM | 0.3926 mL | 1.9632 mL | 3.9263 mL | |
| 10 mM | 0.1963 mL | 0.9816 mL | 1.9632 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.
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BLU9931 is active in vitro in the FGF19-overexpressing PDX-derived cell lines. Cancer Discov. 2015 Apr;5(4):424-37. |
Treatment with BLU9931 leads to tumor regression in the FGF19-overexpressing PDX-derived xenograft LIXC012. Cancer Discov. 2015 Apr;5(4):424-37. |
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