BLU9931

FGFR4 inhibitor,potent and irreversible CAS# 1538604-68-0

BLU9931

Catalog No. BCC3979----Order now to get a substantial discount!

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Chemical structure

BLU9931

3D structure

Chemical Properties of BLU9931

Cas No. 1538604-68-0 SDF Download SDF
PubChem ID 72710839 Appearance Powder
Formula C26H22Cl2N4O3 M.Wt 509.38
Type of Compound N/A Storage Desiccate at -20°C
Solubility DMSO : 83.33 mg/mL (163.59 mM; Need ultrasonic)
H2O : < 0.1 mg/mL (insoluble)
Chemical Name N-[2-[[6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl]amino]-3-methylphenyl]prop-2-enamide
SMILES CC1=C(C(=CC=C1)NC(=O)C=C)NC2=NC=C3C=C(C=CC3=N2)C4=C(C(=CC(=C4Cl)OC)OC)Cl
Standard InChIKey TXEBNKKOLVBTFK-UHFFFAOYSA-N
Standard InChI 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)
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of BLU9931

DescriptionBLU9931 is a potent, selective, and irreversible FGFR4 inhibitor with IC50 of 3 nM, about 297-, 184-, and 50-fold selectivity over FGFR1/2/3, respectively.In Vitro:In MDA-MB-453 cells, BLU9931 potently inhibits phosphorylation of FGFR4 signaling pathway. BLU9931 inhibits proliferation of HCC cell lines that express an intact FGFR4 signaling complex, such as Hep 3B, HUH-7, and JHH-7 cell lines, with EC50 of <1 μM. BLU9931 also inhibits proliferation in PDX-derived cell lines with an intact FGFR4 signaling pathway[1]. BLU9931 induces tumor shrinkage in hepatocellular carcinoma models that express a functioning ligand/receptor complex consisting of FGF19/FGFR4/KLB and adds to a growing list of anti-FGFR4 agents[2].In Vivo:BLU9931 (300 mg/kg, p.o.) leads to tumor regression and prevents this weight loss in mice bearing the FGF19-amplified Hep 3B liver tumors. In mice bearing the FGF19-overexpressing PDX-derived LIXC012 xenografts, treatment with BLU9931 (300 mg/kg, p.o.) also leads to tumor regression[1].

References:
[1]. Hagel M, et al. First Selective Small Molecule Inhibitor of FGFR4 for the Treatment of Hepatocellular Carcinomas with an Activated FGFR4 Signaling Pathway. Cancer Discov. 2015 Apr;5(4):424-37. [2]. Packer LM, et al. Paralog-Specific Kinase Inhibition of FGFR4: Adding to the Arsenal of Anti-FGFR Agents. Cancer Discov. 2015 Apr;5(4):355-7.

Protocol

Kinase Assay [1]
FGFR kinase inhibition assays are performed at KM for ATP. Picomolar to low nanomolar concentrations of FGFR proteins are incubated in 1× Kinase Reaction Buffer (KRB) with 1 μM of CSKtide and 50 to 250 of μM ATP at 25°C for 90 minutes in the presence or absence of a dosed concentration series of inhibitor. All reactions are terminated by the addition of Stop buffer, and plates are read on a Caliper EZReader2. IC50 values are fit with a four-parameter log[Inhibitor] versus response model with floating Hill Slope.

Cell Assay [1]
established and PDX-derived HCC cell lines are 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 is determined by CellTiter-Glo, and results represented as background-subtracted relative light units normalized to a DMSO-treated control. Relative EC50 values are determined at 50% inhibition between the top and bottom plateau of the dose-response curve.

Animal Administration [1]
BLU9931 is formulated in 0.5% carboxymethylcellulose/1% Tween 80 and dosed orally as a suspension twice daily. Sorafenib is dissolved in Cremaphor:EtOH (1:1) and diluted with saline or water to yield the stock solution. Sorafenib is dosed orally once daily. All compound doses are expressed as mg/kg free base. For PK-PD studies, 3 mice are included in each treatment group. Mice receive four doses of compound or vehicle. Blood and tumors are collected 8, 12, 20, and 24 hours following the last dose. The concentration of BLU9931 in plasma is determined by LC/MS-MS. A section of each tumor is immediately frozen in liquid nitrogen and stored at −80°C.

References:
[1]. Hagel M, et al. First Selective Small Molecule Inhibitor of FGFR4 for the Treatment of Hepatocellular Carcinomas with an Activated FGFR4 Signaling Pathway. Cancer Discov. 2015 Apr;5(4):424-37. [2]. Packer LM, et al. Paralog-Specific Kinase Inhibition of FGFR4: Adding to the Arsenal of Anti-FGFR Agents. Cancer Discov. 2015 Apr;5(4):355-7.

BLU9931 Dilution Calculator

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Preparing Stock Solutions of BLU9931

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 1.9632 mL 9.8159 mL 19.6317 mL 39.2634 mL 49.0793 mL
5 mM 0.3926 mL 1.9632 mL 3.9263 mL 7.8527 mL 9.8159 mL
10 mM 0.1963 mL 0.9816 mL 1.9632 mL 3.9263 mL 4.9079 mL
50 mM 0.0393 mL 0.1963 mL 0.3926 mL 0.7853 mL 0.9816 mL
100 mM 0.0196 mL 0.0982 mL 0.1963 mL 0.3926 mL 0.4908 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on BLU9931

BLU9931 is a potent and irreversible inhibitor of FGFR4. BLU9931 potently inhibited FGFR4 activity (IC50 = 3 nmol/L), but weakly inhibited FGFR1 (IC50 = 591 nmol/L), FGFR2 (IC50 = 493 nmol/L), and FGFR3 (IC50 = 150 nmol/L) activity.
Fibroblast growth factor receptor 4 (FGFR4) is the receptor of fibroblast growth factor 19 (FGF19), which is a tightly controlled hormone that regulates bile acid synthesis and hepatocyte proliferation in the normal liver. FGFR4 acts as a targeted therapy to treat patients with HCC whose tumors have an activated FGFR4 signaling pathway. BLU9931 is highly selective for FGFR4 versus other FGFR family members and all other kinases. BLU9931 binds within the ATP-binding pocket of FGFR4, forming a covalent bond with Cys552. The anilino-quinazoline core of BLU9931 makes a bidentate hydrogen-bonding interaction with the hinge residue (Ala553) of FGFR4, whereas the dichlorodimethoxyphenyl group occupies the hydrophobic pocket, providing FGFR-family selectivity. BLU9931 displayed significant binding to only two of the 398 wild-type kinases, FGFR4 (99.7% inhibition relative to DMSO control; Kd = 6 nmol/L) and CSF1R (90.1% inhibition relative to DMSO control; Kd = 2716 nmol/L) by KINOMEscan method. [2]
BLU9931 shows remarkable antitumor activity in mice bearing an HCC tumor xenograft that overexpresses FGF19 due to amplification as well as a liver tumor xenograft that overexpresses FGF19 mRNA but lacks FGF19 amplification.
References:
[1]. Hagel M, Miduturu C, Sheets M et al.First Selective Small Molecule Inhibitor of FGFR4 for the Treatment of Hepatocellular Carcinomas with an Activated FGFR4 Signaling Pathway. Cancer Discov. 2015 Mar 16. [Epub ahead of print]
[2]. Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP. Comprehensive analysis of kinase inhibitor selectivity. Nat Biotechnol. 2011 Oct 30;29(11):1046-51.

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References on BLU9931

Design, Synthesis and Anti-Proliferative Activities of 2,6-Substituted Thieno[3,2-d]pyrimidine Derivatives Containing Electrophilic Warheads.[Pubmed:28498316]

Molecules. 2017 May 12;22(5). pii: molecules22050788.

Thieno[3,2-d]pyrimidine as an effective pharmacophore has been extensively studied. However, its 2,6-substituted derivatives are rarely reported. In the present study, eighteen 2,6-substituted thieno[3,2-d]pyrimidine derivatives containing electrophilic warheads were designed based on the first known Fibroblast growth factor receptor-4 (FGFR4) inhibitor BLU9931. Unexpectedly, all of the derivatives exhibited negligible activity against FGFR4. However, most of the target compounds exhibited antiproliferative activities against four human cancer cell lines, including A431, NCI-H1975, Ramos and SNU-16. Compound 12 showed the most potent antiproliferative activities on the above four cell lines with IC50 values of 1.4 muM, 1.2 muM, 0.6 muM, and 2.6 muM, respectively. Additionally, the antiproliferative activity of 12 against MDA-MB-221 proved that 12 had the selectivity towards certain tumor cell lines. Furthermore, preliminary structure-activity relationship analysis was discussed based on the experimental data.

Implications of FGF19 on sorafenib-mediated nitric oxide production in hepatocellular carcinoma cells - a short report.[Pubmed:28983785]

Cell Oncol (Dordr). 2018 Feb;41(1):85-91.

BACKGROUND: Hepatocellular carcinoma (HCC), a primary neoplasm derived from hepatocytes, is the second leading cause of cancer mortality worldwide. Previous work has shown that fibroblast growth factor 19 (FGF19), an oncogenic driver, acts as a negative regulator of the therapeutic efficacy of the tyrosine kinase inhibitor sorafenib in HCC cells. The FGF19-mediated mechanism affecting sorafenib treatment, however, still remains to be resolved. Here, we hypothesize that the FGF19-FGFR4 axis may affect the effectiveness of sorafenib in the treatment of HCC. METHODS: FGF19 and FGFR4 cDNAs were cloned into a pcDNA3.1 vector and subsequently used for exogenous over-expression analyses. FGF19 knockdown cells were generated using a lentiviral-mediated short hairpin RNA (shRNA) methodology and FGFR4 knockout cells were generated using a CRISPR-Cas9 methodology. FGFR4 activation in HCC cells was inhibited by BLU9931. The effects of exogenous gene over-expression, expression knockdown and knockout, as well as drug efficacies in HCC cells, were validated using Western blotting. HCC cell proliferation was assessed using a CellTiter 96((R)) AQueous One Solution Cell Proliferation Assay, whereas NO levels were assessed using DAF-FM DA staining in conjunction with electrochemical biosensors. RESULTS: We found that FGF19, when exogenously overexpressed, results in a reduced sorafenib-induced NO generation and a decreased proliferation of HCC cells. In contrast, we found that either FGF19 silencing or knockout of its receptor FGFR4 sensitized HCC cells to sorafenib through the induction of NO generation. Concordantly, we found that inactivation of FGFR4 by BLU9931 enhanced the sensitivity of HCC cells to sorafenib. CONCLUSION: From our data we conclude that the FGF19-FGFR4 axis may play a critical role in the effects elicited by sorafenib in HCC cells. Blocking the FGF19-FGFR4 axis may provide novel opportunities to improve the efficacy of sorafenib in the treatment of patients with HCC.

Paralog-Specific Kinase Inhibition of FGFR4: Adding to the Arsenal of Anti-FGFR Agents.[Pubmed:25847957]

Cancer Discov. 2015 Apr;5(4):355-7.

In this issue of Cancer Discovery, Hagel and colleagues report the design and the in vitro and in vivo activity of a novel, irreversible, paralog-specific kinase inhibitor of FGFR4, BLU9931. This compound binds covalently to a cysteine residue in the hinge region of FGFR4 but not in FGFR1-3. BLU9931 induces tumor shrinkage in hepatocellular carcinoma models that express a functioning ligand/receptor complex consisting of FGF19/FGFR4/KLB and adds to a growing list of anti-FGFR4 agents.

FGFR inhibitors: Effects on cancer cells, tumor microenvironment and whole-body homeostasis (Review).[Pubmed:27245147]

Int J Mol Med. 2016 Jul;38(1):3-15.

Fibroblast growth factor (FGF)2, FGF4, FGF7 and FGF20 are representative paracrine FGFs binding to heparan-sulfate proteoglycan and fibroblast growth factor receptors (FGFRs), whereas FGF19, FGF21 and FGF23 are endocrine FGFs binding to Klotho and FGFRs. FGFR1 is relatively frequently amplified and overexpressed in breast and lung cancer, and FGFR2 in gastric cancer. BCR-FGFR1, CNTRL-FGFR1, CUX1-FGFR1, FGFR1OP-FGFR1, MYO18A-FGFR1 and ZMYM2-FGFR1 fusions in myeloproliferative neoplasms are non-receptor-type FGFR kinases, whereas FGFR1-TACC1, FGFR2-AFF3, FGFR2-BICC1, FGFR2-PPHLN1, FGFR3-BAIAP2L1 and FGFR3-TACC3 fusions in solid tumors are transmembrane-type FGFRs with C-terminal alterations. AZD4547, BGJ398 (infigratinib), Debio-1347 and dovitinib are FGFR1/2/3 inhibitors; BLU9931 is a selective FGFR4 inhibitor; FIIN-2, JNJ-42756493, LY2874455 and ponatinib are pan-FGFR inhibitors. AZD4547, dovitinib and ponatinib are multi-kinase inhibitors targeting FGFRs, colony stimulating factor 1 receptor (CSF1R), vascular endothelial growth factor (VEGF)R2, and others. The tumor microenvironment consists of cancer cells and stromal/immune cells, such as cancer-associated fibroblasts (CAFs), endothelial cells, M2-type tumor-associating macrophages (M2-TAMs), myeloid-derived suppressor cells (MDSCs) and regulatory T cells. FGFR inhibitors elicit antitumor effects directly on cancer cells, as well as indirectly through the blockade of paracrine signaling. The dual inhibition of FGF and CSF1 or VEGF signaling is expected to enhance the antitumor effects through the targeting of immune evasion and angiogenesis in the tumor microenvironment. Combination therapy using tyrosine kinase inhibitors (FGFR or CSF1R inhibitors) and immune checkpoint blockers (anti-PD-1 or anti-CTLA-4 monoclonal antibodies) may be a promising choice for cancer patients. The inhibition of FGF19-FGFR4 signaling is associated with a risk of liver toxicity, whereas the activation of FGF23-FGFR4 signaling is associated with a risk of heart toxicity. Endocrine FGF signaling affects the pathophysiology of cancer patients who are prescribed FGFR inhibitors. Whole-genome sequencing is necessary for the detection of promoter/enhancer alterations of FGFR genes and rare alterations of other genes causing FGFR overexpression. To sustain the health care system in an aging society, a benefit-cost analysis should be performed with a focus on disease-free survival and the total medical cost before implementing genome-based precision medicine for cancer patients.

First Selective Small Molecule Inhibitor of FGFR4 for the Treatment of Hepatocellular Carcinomas with an Activated FGFR4 Signaling Pathway.[Pubmed:25776529]

Cancer Discov. 2015 Apr;5(4):424-37.

UNLABELLED: Aberrant signaling through the fibroblast growth factor 19 (FGF19)/fibroblast growth factor receptor 4 (FGFR 4) signaling complex has been shown to cause hepatocellular carcinoma (HCC) in mice and has been implicated to play a similar role in humans. We have developed BLU9931, a potent and irreversible small-molecule inhibitor of FGFR4, as a targeted therapy to treat patients with HCC whose tumors have an activated FGFR4 signaling pathway. BLU9931 is exquisitely selective for FGFR4 versus other FGFR family members and all other kinases. BLU9931 shows remarkable antitumor activity in mice bearing an HCC tumor xenograft that overexpresses FGF19 due to amplification as well as a liver tumor xenograft that overexpresses FGF19 mRNA but lacks FGF19 amplification. Approximately one third of patients with HCC whose tumors express FGF19 together with FGFR4 and its coreceptor klotho beta (KLB) could potentially respond to treatment with an FGFR4 inhibitor. These findings are the first demonstration of a therapeutic strategy that targets a subset of patients with HCC. SIGNIFICANCE: This article documents the discovery of BLU9931, a novel irreversible kinase inhibitor that specifically targets FGFR4 while sparing all other FGFR paralogs and demonstrates exquisite kinome selectivity. BLU9931 is efficacious in tumors with an intact FGFR4 signaling pathway that includes FGF19, FGFR4, and KLB. BLU9931 is the first FGFR4-selective molecule for the treatment of patients with HCC with aberrant FGFR4 signaling.

Description

BLU9931 is a potent, highly selective, and irreversible fibroblast growth factor receptor 4 (FGFR4) inhibitor with an IC50 of 3 nM and a Kd of 6 nM. BLU9931 has significant antitumor activity.

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