R428 (BGB324)

R428 (BGB324) is an inhibitor of Axl with IC50 of 14 nM, >100-fold selective for Axl versus Abl. Selectivty for Axl is also greater than Mer and Tyro3 (50-to-100- fold more selective) and InsR, EGFR, HER2, and PDGFRβ (100- fold more selective).

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R428 (BGB324) Chemical Structure

R428 (BGB324) Chemical Structure
Molecular Weight: 506.64

Validation & Quality Control

Customer Product Validation(2)

Quality Control & MSDS

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R428 (BGB324) is available in the following compound libraries:

Product Information

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  • Research Area
  • Inhibition Profile

Product Description

Biological Activity

Description R428 (BGB324) is an inhibitor of Axl with IC50 of 14 nM, >100-fold selective for Axl versus Abl. Selectivty for Axl is also greater than Mer and Tyro3 (50-to-100- fold more selective) and InsR, EGFR, HER2, and PDGFRβ (100- fold more selective).
Targets Axl [1]
IC50 14 nM
In vitro R428 blocks the catalytic and procancerous activities of Axl. R428 inhibits Axl with low nanomolar activity and blocks Axl-dependent events, including Akt phosphorylation, breast cancer cell invasion, and proinflammatory cytokine production. [1] In a recent study, the Axl inhibitor R428 shows a mean IC50 dose of ∼ 2.0μM for the primary CLL B cells after 24 hours of treatment and normal B-, T-, and natural killer (NK) cells show no significant amount of cell death at this dose of R428 (2.5 μM) under similar experimental conditions. [2]
In vivo Pharmacologic investigations reveal favorable exposure after oral administration such that R428-treated tumors display a dose-dependent reduction in expression of the cytokine granulocyte macrophage colony-stimulating factor and the epithelial-mesenchymal transition transcriptional regulator Snail. In support of an earlier study, R428 inhibits angiogenesis in corneal micropocket and tumor models. R428 administration reduces metastatic burden and extends survival in MDA-MB-231 intracardiac and 4T1 orthotopic (median survival, >80 days compared with 52 days; P < 0.05) mouse models of breast cancer metastasis. [1]
Features

Protocol(Only for Reference)

Kinase Assay: [1]

In vitro Kinase Assays A five-point R428 dose titration is performed in radiometric in vitro kinase assays on 133 kinases at the KmATP for each kinase. Axl, Mer, and Tyro3 assays are also performed using a fluorescence polarization protocol. HER2 activity is determined by Z'-LYTE assay.

Animal Study: [1]

Animal Models MDA-MB-231-luc-D3H2LN Intracardiac Model
Formulation 0.5% hydroxypropylmethylcellulose + 0.1% Tween 80
Dosages 125 mg/kg
Administration Oral, twice daily

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Holland SJ, et al. Cancer Res, 2010, 70(4), 1544-1554.

[2] Ghosh AK, et al. Blood, 2011, 117(6), 1928-1937.

Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2015-08-29)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT02424617 Recruiting Non-Small Cell Lung Cancer BerGenBio AS March 2015 Phase 1|Phase 2
NCT02488408 Recruiting Acute Myeloid Leukemia BerGenBio AS September 2014 Phase 1

Chemical Information

Download R428 (BGB324) SDF
Molecular Weight (MW) 506.64
Formula

C30H34N8

CAS No. 1037624-75-1
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms
Solubility (25°C) * In vitro DMSO 60 mg/mL (118.42 mM)
Water <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)
In vivo
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name 1H-1,2,4-Triazole-3,5-diamine, 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N3-[(7S)-6,7,8,9-tetrahydro-7-(1-pyrrolidinyl)-5H-benzocyclohepten-2-yl]-

Customer Product Validation (2)


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Rating
Source Cancer Res 2014 74(18), 5152-64. R428 (BGB324) purchased from Selleck
Method Western blot
Cell Lines HP cells
Concentrations 0-1.0 uM
Incubation Time 24 h
Results The small-molecule TKI R428, which has greater than 100-fold selectivity for AXL as compared with EGFR or Tyro and 50-fold greater affinity than Mer. R428 treatment led to a loss of EGFR phosphorylation on tyrosine 1068 and MAPK signaling, whereas these targets were relatively unaffected in HP cells.

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Rating
Source Biochem Bioph Res Co 2014 10.1016/j.bbrc.2014.10.126. R428 (BGB324) purchased from Selleck
Method Western blot, Annexin V
Cell Lines NB1643 cells
Concentrations 300 nM
Incubation Time 48 h
Results To further explore the application of Axl-specific small-molecule inhibitor in ALK-targeted therapy, we treated cells with BGB324 (an Axl inhibitor) in the presence of crizotinib (A)or ceritinib (B) and the frequency of apoptosis was measured by Annexin V binding assay. phosphorylated Axl and ALK were effectively suppressed by BGB324 and crizotinib respectively in NB1643 cells(C). Notably, combination treatment resulted in marked inhibition of the activities of Axl and ALK, as well as more efficiency in induction of activated-caspase3 than either single-drug alone, consistent with the increased apoptosis observed in the annexin V binding assay (A). Similar results were observed in the SHSY5Y cell lines (D), with combination treatment showing marked inhibition of phosphorylated Axl and ALK, as well as increased caspase3 cleavage.

Product Use Citation (5)

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