Axl is a member of the TAM (Tyro3, Axl, Mer) receptor tyrosine kinase (RTK) family and Axl signaling stimulates cellular responses and results in invasion, migration, survival signaling, angiogenesis, cell transformation, and proliferation associated with cancer. R428 (BGB324) is an inhibitor of Axl with IC50 of 14 nM by blocking the catalytic and procancerous activities with low nanomolar activity. R428-treated tumors reduce expression of the cytokine granulocyte macrophage colony-stimulating factor and angiogenesis in corneal micropocket and tumor model as well as metastatic burden and extends survival in MDA-MB-231 intracardiac and 4T1 orthotopicmouse models of breast cancer. The mean IC50 for the primary CLL B cells is of ~2.0 μM of R428 treatment and no significant amount of cell death of normal B-, T-, natural killer (NK) cells were observed at this dose of 2.5 μM. R428 inhibited Axl phosphorylation by 50%-60% in CLL B cells at a dose of 1.0 μM for overnight suggesting R428 can target Axl phosphorylation and are responsible for apoptosis induction in CLL B cells. Furthermore, a substantial level of reduction in Mcl-1 in all the 3 CLL B-cell lysates (P5-P7) treated with R428 in both a dose- and time dependent manner. Besides, R428 inhibited growth of H1299 with an IC50 of approximately 4 μM while LDC1267 had no effects on the cell growth even at 20 μM. R428 induced a series of apoptotic events, including caspase-8/9 activation, PARP cleavage, and upregulation of anti-apoptotic proteins Bcl-xl and Bcl-2 in the Hela cells. R428 treatment also increased the autophagy level of LC3-II, indicating the induction of autophagy initiation, but did not decrease the level of p62, suggesting a blockage of autophagic degradation. Further analyses revealed that R428 blocked lysosomal acidification and recycling, accumulated autophagosomes and lysosomes, and induced cell apoptosis.
Bemcentinib/贝森替尼 细胞实验
Cell Line
Concentration
Treated Time
Description
References
BRAFV600-mutant melanoma short-term cultures
2 μM
4 days
To verify the resistance of MITF-low/NF-κB-high melanoma short-term cultures to RAF and MEK inhibitors.
Cancer Discov. 2014 Jul;4(7):816-27.
BRAFV600-mutant melanoma cell lines
2 μM
4 days
To assess the sensitivity of BRAFV600-mutant melanoma cell lines to the RAF inhibitor PLX4720, finding that MITF-high cell lines were sensitive to PLX4720, while MITF-low/NF-κB-high cell lines were resistant.
Cancer Discov. 2014 Jul;4(7):816-27.
ER3
1.2 μM
16 h
To evaluate the effect of Bemcentinib on autophagic flux in ER3 cells, results showed that Bemcentinib significantly reduced the starvation-induced degradation of long-lived proteins, indicating the blockage of autophagic flux.
J Thorac Oncol. 2020 Jun;15(6):973-999.
HCC827
0.8 μM
24 h
To investigate the effect of Bemcentinib on autophagic flux in HCC827 cells, results showed that Bemcentinib treatment increased the numbers of LC3A/B-positive autophagosomes and lysosomes, indicating the blockage of autophagic flux.
J Thorac Oncol. 2020 Jun;15(6):973-999.
344SQ_Z-cad cells
2 μM
72 h
Bemcentinib specifically killed GFP+ mesenchymal cells, while selumetinib specifically killed RFP+ epithelial cells. Combination treatment significantly increased the total amount of cell death and killed both subpopulations to a greater degree than either single agent.
Cancer Res. 2021 Mar 1;81(5):1398-1412.
MCF-7/ADR cells
1 µM
24 h
To evaluate the inhibitory effect of R428 on Axl activity and its impact on the expression of epithelial and mesenchymal markers in MCF-7/ADR cells. Results showed that R428 significantly inhibited Axl activity and reduced the expression of mesenchymal markers N-cadherin and Vimentin.
Theranostics. 2016 May 24;6(8):1205-19.
BaF3-EpoR-JAK2V617F cells
0.5, 1, 2, 3, 4, 5 µM
48 h
To assess the effect of Bemcentinib on the viability of BaF3-EpoR-JAK2V617F cells, the results showed that Bemcentinib significantly reduced cell viability.
Hemasphere. 2021 Aug 11;5(9):e630.
SET-2 cells
0.5, 1, 2, 3, 4, 5 µM
48 h
To assess the effect of Bemcentinib on the viability of SET-2 cells, the results showed that Bemcentinib significantly reduced cell viability.
Hemasphere. 2021 Aug 11;5(9):e630.
BMDCs
40 nM
24 h
BGB324-treated BMDCs showed increased secretion of IFN-b, indicating that Axl inhibition promotes type I interferon production.
Cell Rep Med. 2022 Mar 15;3(3):100554.
PC9 cells
100 nM
7 days
To assess cell viability, the results showed that Bemcentinib inhibited the viability of PC9 cells.
Cell Rep Med. 2024 Sep 17;5(9):101703.
PC9 cells
100 nM
72 h
To assess cell viability, the results showed that Bemcentinib inhibited the viability of PC9 cells.
Cell Rep Med. 2024 Sep 17;5(9):101703.
Human endometrial stromal cells (hESCs)
1 µM
72 h
Bemcentinib inhibited AXL activation and significantly reduced the expression of Collagen 1 and α-SMA, indicating the importance of the AXL pathway in GAS6 functioning.
EMBO Mol Med. 2023 Sep 11;15(9):e17601.
Bemcentinib/贝森替尼 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Nude mice
HCC827 xenograft model
Oral
50 mg/kg or 100 mg/kg
Twice daily for 5 months
To evaluate the effect of Bemcentinib on EGFR inhibitor resistance in the HCC827 xenograft model, results showed that Bemcentinib significantly delayed the onset of tumor resistance to erlotinib.
J Thorac Oncol. 2020 Jun;15(6):973-999.
Mice
344SQ_Z-cad subcutaneous tumor model
Oral
100 mg/kg
Daily for 3-4 weeks
The combination of bemcentinib and selumetinib significantly suppressed tumor growth and had a significant impact on tumor growth throughout the duration of treatment. The combination treatment also significantly reduced the formation of lung metastatic nodules, indicating its inhibitory effect on tumor metastasis.
Cancer Res. 2021 Mar 1;81(5):1398-1412.
BALB/c nude mice
MCF-7/ADR cell subcutaneous xenograft model
Oral
25 mg/kg
Twice daily for 30 days
To evaluate the inhibitory effect of R428 on the growth of MCF-7/ADR cell subcutaneous xenografts. Results showed that R428 significantly inhibited tumor growth and reduced the number of lung metastatic nodules.
Theranostics. 2016 May 24;6(8):1205-19.
NSG mice
SET-2 xenograft model
Oral
50 mg/kg
Twice daily until tumors reached 1500 mm3
To assess the effect of Bemcentinib on tumor growth in the SET-2 xenograft model, the results showed that Bemcentinib significantly inhibited tumor growth.
Hemasphere. 2021 Aug 11;5(9):e630.
Mice
KPL tumor model
Oral
50 mg/kg
Twice daily for 7 days
Combination therapy of BGB324 with anti-PD-1 significantly controlled the growth of KPL tumors and increased the infiltration of TCF1+PD-1+CD8 T cells in the tumor.
Cell Rep Med. 2022 Mar 15;3(3):100554.
Mice
PC9 cell xenograft model
Oral
50 mg/kg
Once daily for 4 weeks
To evaluate the effect of Bemcentinib on tumor relapse, the results showed that Bemcentinib was unable to persistently block relapses.
Cell Rep Med. 2024 Sep 17;5(9):101703.
Mice
NSG mice
Oral
50 mg/kg
Twice daily, continued treatment
To study the effect of Bemcentinib on JAK2 inhibitor resistant mouse models, results showed that Bemcentinib significantly inhibited tumor growth.
Clin Cancer Res. 2024 Feb 1;30(3):586-599.
Mice
IUA mouse model
Oral
80 mg/kg
Started 7 days after the first curettage and continued until the end of the experiment
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