R428 blocks the catalytic and procancerous activities of Axl. R428 inhibits Axl with low nanomolar activity and blocked Axl-dependent events, including Akt phosphorylation, breast cancer cell invasion, and proinflammatory cytokine production. R428 inhibited angiogenesis in corneal micropocket and tumor models. In vitro, R428 caused a concentration-dependent inhibition of preadipocyte differentiation into mature adipocytes, as evidenced by reduced lipid uptake. In vivo, oral administration of R428 for 5 weeks to mice kept on a high-fat diet resulted in significantly reduced weight gain and subcutaneous and gonadal fat mass. Additionally, R428 synergized with cisplatin to enhance suppression of liver micrometastasis.
|Cell lines||MDA-MB-231 or 4T1 cells|
|Preparation method||Invasion Assays: MDA-MB-231 or 4T1 cells (1 × 105) were allowed to migrate through Matrigel (Millipore) toward 20% FCS in an 8-μm pore 24-well Transwell plate (BD Bio‐sciences) at 37°C for 16 to 24 h. Noninvaded cells and Matrigel were removed by swabbing. Invaded cells were fixed in 4% formaldehyde, stained with 1% crystal violet, and quantified as for Axl cellbased assay. Cells were preincubated with R428 for 3 h. R428 was added to both upper and lower Transwell chambers.|
|Concentrations||0, 0.03, 0.3, 3 µ M|
|Incubation time||3 h|
|Animal models||Female BALB/c mice 4T1 Orthotopic Model|
|Formulation||R428 was formulated for in vivo studies in 0.5% hydroxypropylmethylcellulose + 0.1% Tween 80.|
|Dosages||7–75 mg/kg twice daily|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|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.
|Solubility||DMSO 100 mg/mL|
|Source||Cancer Biology& Therapy (2015) . Figure 6.R428 (Abmole Bioscience, Houston, TX)|
|Method||Western blot and MTT assay|
|Cell Lines||MDA-MB-231 cells and MDA-MB-231 cells that were transfected with CTL or ARF1 siRNA|
|Concentrations||1 µ M|
|Incubation Time||western blot (1 h) and MTT assay (24 h)|
|Results||Interestingly, like in the EGFR inhibitor treatment, the AXL inhibitor, R428, was effective to enhance ARF1 activity. But, more importantly, this inhibitor blocked gefitinib-induced ARF1 activation. Finally, this observation was also found in MDA-MB-157 cells. However, in cells co-treated with the AXL inhibitor, R428, and gefitinib, the depletion of ARF1 was shown to have no effect further suggesting that ARF1 is signaling downstream of AXL in gefitinib treated cells (Figure 6F).|
Cancer Biol Ther. 2015 Oct;1535-47.
Growth arrest-specific protein 6 receptor antagonism impairs adipocyte differentiation and adipose tissue development in mice.
Lijnen HR, et al. J Pharmacol Exp Ther. 2011 May;337(2):457-64. PMID: 21285281.
The novel receptor tyrosine kinase Axl is constitutively active in B-cell chronic lymphocytic leukemia and acts as a docking site of nonreceptor kinases: implications for therapy.
Ghosh AK, et al. Blood. 2011 Feb 10;117(6):1928-37. PMID: 21135257.
R428, a selective small molecule inhibitor of Axl kinase, blocks tumor spread and prolongs survival in models of metastatic breast cancer.
Holland SJ, et al. Cancer Res. 2010 Feb 15;70(4):1544-54. PMID: 20145120.
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