Dubermatinib

Biological Activity

TP-0903 is a potent and selective AXL inhibitor with an IC50 value of 27 nM. TP-0903 induces massive apoptosis in CLL B cells with LD50 values of nanomolar ranges.

In vitro: TP-0903 shows extremely potent activity in cell viability assays with an IC50 of 6 nM against the pancreatic cancer cell line PSN-1. TP-0903 is evaluated for its ability to block GAS6-mediated activation of AXL in pancreatic cancer cells. PSN-1 cells are serum-starved and then stimulated with GAS6 in the presence of various concentrations of TP-0903.

Product Citations

• 

  CNS Neurosci Ther. 2020 Jul;26(7):777.

  Retraction: Receptor tyrosine kinase AXL is correlated with poor prognosis and induces temozolomide resistance in glioblastoma
  Dubermatinib purchased from AbMole

• 

  CNS Neurosci Ther. 2019 Oct 2.

  Receptor tyrosine kinase AXL is correlated with poor prognosis and induces temozolomide resistance in glioblastoma.
  Dubermatinib purchased from AbMole

Customer Product Validations & Biological Datas

	Source	CNS Neurosci Ther (2020 Jul). Figure 5.TP-0903 (Abmole Bioscience, TX, USA)
	Method	In vitro cell viability assay
	Cell Lines	GBM cells
	Concentrations	different concentrations
	Incubation Time	3 days
	Results	Moreover, an in vitro proliferation assay indicated that TP-0903 attenuated the growth of TMZ-resistant U87 cells, and more importantly, the gained TMZ resistance was significantly reversed by TP-0903.

Protocol

Cell Experiment
Cell lines	PSN-1 cells
Preparation method	For cell proliferation assays, 45 µL containing 1000 cells per well are seeded into solid white 384-well plates in appropriate cell growth media containing 10% FBS and incubated overnight at 37 °C and 5% CO2. The following day, test compounds are diluted in serum free growth media to 10x desired concentrations and 5 µL is added to each well. Combined compound and cells are incubated for 96 hours. Following incubation, 40 µL of ATP-Lite solution is added to each well, incubated for an additional 10 minutes at room temperature and luminescence is measured on an EnVision microplate reader. Percent cell viability for test compounds is calculated by comparing treated wells to appropriate controls (e.g. vehicle treated) included on each plate.
Concentrations
Incubation time	96 hours

Animal Experiment
Animal models	Female nude mice (6 weeks old) carrying GBM cells
Formulation	-
Dosages	20 mg/kg/d
Administration	tail vein injection

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 K_m factor for a mouse and then divide by the K_m factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.

Chemical Information

References

[1] Sinha S, et al. Clin Cancer Res. Targeted Axl Inhibition Primes Chronic Lymphocytic Leukemia B Cells to Apoptosis and Shows Synergistic/Additive Effects in Combination with BTK Inhibitors.