ChemicalBook Product Catalog Biochemical Engineering Inhibitors protein tyrosine kinase R428

R428

Product NameR428
CAS1037624-75-1
MFC30H34N8
MW506.64
EINECS
MOL File1037624-75-1.mol

Chemical Properties

Melting point	>211°C (dec.)
Boiling point	799.6±70.0 °C(Predicted)
Density	1.41±0.1 g/cm3(Predicted)
storage temp.	-20°C
solubility	Soluble in DMSO (up to at least 25 mg/ml)
pka	10.34±0.20(Predicted)
form	Yellow powder.
color	Yellow
Stability	Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 3 months.
InChIKey	KXMZDGSRSGHMMK-VWLOTQADSA-N
SMILES	N1(C2=NN=C3C4=CC=CC=C4CCCC3=C2)C(N)=NC(NC2=CC=C3CC[C@H](N4CCCC4)CCC3=C2)=N1

Usage And Synthesis

Description

R428 (bemcentinib, BGB324), a selective small-molecule inhibitor of AXL, is currently being evaluated in phase II trials for the treatment of non-small-cell lung cancer (NSCLC) and acute myelocytic leukemia (AML). It has been found to induce apoptosis in cancer cells and to block tumor spread in models of metastatic breast cancer. The therapeutic potential of R428 has also been demonstrated in highly invasive esophageal adenocarcinoma cells and in ESCC cells.
R428 is a selective, small molecule inhibitor of Axl that blocks its catalytic and precancerous activities. R428 treatment reduced Axl-induced AKT phosphorylation, cancer cell invasion, angiogenesis, and the production of pro-inflammatory cytokines. It also reduced the expression of the cytokine granulocyte macrophage colony-stimulating factor and Snail in a dosage-dependent manner. Interestingly,using R428 to inhibit Axl-mediated cellular and molecular functions during cisplatin treatments achieved an enhanced suppression of liver metastases. Axl knockdowns in RAC cell lines reduced migration, invasion, and in vivo engraftment, accompanied by a downregulation in the activity of the Ral GTPase proteins (RalA and RalB). Similar effects were obtained using an A428 inhibitor. Blocking Axl functions also abrogated the phosphorylation of ERBB2 (Her-2/neu) at the Tyr877 residue, which reveals the cross-functional effects of R428 on different receptor signaling axes.
Cabozantinib (XL184) and R428 (BGB324) Inhibit the Growth of Esophageal Squamous Cell Carcinoma (ESCC)

Uses

R 428 is an AXL tyrosine kinase inhibitor shown to be used as an anti-cancer agent.

in vivo

Bemcentinib (R428) (125 mg/kg, p.o.) significantly blocks MDA-MB-231-luc-D3H2LN metastases development in two independent mouse models of breast cancer dissemination, suppresses both tumor angiogenesis and vascular endothelial growth factor (VEGF)-induced corneal neovascularization in vivo^[2].
Bemcentinib (R428) (75 mg/kg/day, 25 mg/kg twice daily, p.o.) makes mice keep on a high-fat diet resulted in significantly reduced weight gain and subcutaneous and gonadal fat mass^[3].

target

Axl

IC 50

Axl

References

[1] SACHA J HOLLAND. R428, a selective small molecule inhibitor of Axl kinase, blocks tumor spread and prolongs survival in models of metastatic breast cancer.[J]. Cancer research, 2010, 70 4: 1544-1554. DOI:10.1158/0008-5472.can-09-2997
[2] EMMY D G FLEUREN. The role of AXL and the in vitro activity of the receptor tyrosine kinase inhibitor BGB324 in Ewing sarcoma.[J]. Oncotarget, 2014, 5 24: 12753-12768. DOI:10.18632/oncotarget.2648
[3] FEI XU Yong S Hongling Li. Inhibition of Axl improves the targeted therapy against ALK-mutated neuroblastoma[J]. Biochemical and biophysical research communications, 2014, 454 4: Pages 566-571. DOI:10.1016/j.bbrc.2014.10.126
[4] ISABEL BEN-BATALLA. Axl Blockade by BGB324 Inhibits BCR-ABL Tyrosine Kinase Inhibitor-Sensitive and -Resistant Chronic Myeloid Leukemia.[J]. Clinical Cancer Research, 2017, 23 1: 2289-2300. DOI:10.1158/1078-0432.ccr-16-1930
[5] JIAN-ZHONG LIN. Targeting AXL overcomes resistance to docetaxel therapy in advanced prostate cancer.[J]. Oncotarget, 2017, 8 25: 41064-41077. DOI:10.18632/oncotarget.17026
[6] ZHIQIANG GUO. Axl inhibition induces the antitumor immune response which can be further potentiated by PD-1 blockade in the mouse cancer models.[J]. Oncotarget, 2017: 89761-89774. DOI:10.18632/oncotarget.21125
[7] KATHLEEN F LUDWIG. Small-Molecule Inhibition of Axl Targets Tumor Immune Suppression and Enhances Chemotherapy in Pancreatic Cancer.[J]. Cancer research, 2018: 246-255. DOI:10.1158/0008-5472.can-17-1973

R428

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