Biological Activity
ONO-7475 is a potent and orally active Axl/Mer inhibitor with IC50 values of 0.7 nM and 1.0 nM, respectively. ONO-7475 sensitizes AXL-overexpressing EGFR-mutant NSCLC cells to the EGFR-TKIs, suppresses the emergence and maintenance of tolerant cells. ONO-7475 combines with Osimertinib provides a bright promise for the study of EGFR-mutated non-small cell lung cancer (NSCLC).
Mice fed a diet containing ONO-7475 exhibited significantly longer survival and, interestingly, blocked leukemia cell infiltration in the liver. In summary, ONO-7475 effectively kills acute myeloid leukemia cells in vitro and in vivo by mechanisms that involve disruption of diverse survival and proliferation pathways.
Protocol
| Cell Experiment |
|---|
| Cell lines |
MOLM13, MV4;11, HL60, OCI-AML3, MOLM13 luc/gfp cells, MOLM13 p53 shRNA cells, BM-MSC |
| Preparation method |
MOLM13 and MV4;11 (FLT3 ITD) and OCI-AML3 (FLT3 WT) cells are incubated with vehicle (0.1% DMSO) or varying doses of ONO-7475 for 48 hours. Viable cell number and apoptosis are measured by flow cytometry. |
| Concentrations |
50-500 nM |
| Incubation time |
24 h, 48 h, 72 h |
| Animal Experiment |
|---|
| Animal models |
4-week old female NSG mice bearing MOLM13 cells |
| Formulation |
diet containing 0.004% and 0.013% ONO-7475 |
| Dosages |
6 mg/kg, 20 mg/kg |
| Administration |
Oral gavage |
Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)
| Species |
Mouse |
Rat |
Rabbit |
Guinea pig |
Hamster |
Dog |
| Weight (kg) |
0.02 |
0.15 |
1.8 |
0.4 |
0.08 |
10 |
| Body Surface Area (m2) |
0.007 |
0.025 |
0.15 |
0.05 |
0.02 |
0.5 |
| Km factor |
3 |
6 |
12 |
8 |
5 |
20 |
| Animal A (mg/kg) = Animal B (mg/kg) multiplied by |
Animal B Km
|
| Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 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 Compound A of 10 mg/kg.
Chemical Information
| Molecular Weight |
562.57 |
| Formula |
C32H26N4O6 |
| CAS Number |
1646839-59-9
|
| Purity |
>99% |
| Solubility |
DMSO 100 mg/mL |
| Storage |
at -20°C
|
References
[1] Naoko Okura, et al. Clin Cancer Res. ONO-7475, a Novel AXL Inhibitor, Suppresses the Adaptive Resistance to Initial EGFR-TKI Treatment in EGFR-Mutated Non-Small Cell Lung Cancer
[2] Peter P Ruvolo, et al. Haematologica. Anexelekto/MER tyrosine kinase inhibitor ONO-7475 arrests growth and kills FMS-like tyrosine kinase 3-internal tandem duplication mutant acute myeloid leukemia cells by diverse mechanisms
