Dubermatinib(TP-0903)

Catalog No.S7846 Batch:S784604

Technical Data

Formula	C₂₄H₃₀ClN₇O₂S
Molecular Weight	516.06	CAS No.	1341200-45-0
Solubility (25°C)*	In vitro	DMSO	3 mg/mL (5.81 mM)
		Ethanol	1 mg/mL (1.93 mM)
		Water	Insoluble
* <1 mg/ml means slightly soluble or insoluble. * Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations. * Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.)

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Biological Activity

Description

TP-0903 is a potent and selective AXL Inhibitor with IC50 of 27 nM. TP-0903 is highly effective in inducing apoptosis.

Targets

Axl ^[1]
(Cell-free assay)

27 nM

In vitro

In pancreatic cancer cells (PSN-1), TP-0903 shows strong antiproliferative activity with IC50 of 6 M. TP-0903 also induces strong G2/M arrest by potently inhibiting Aurora A and B. [1] In CLL B cells from all the patients with CLL, TP-0903 causes a dose-dependent induction of massive apoptosis by targeting phosphorylated Axl, and overcomes CLL BMSC-mediated protection of CLL B cells from apoptosis. ^[2]

In vivo

In the adult rat hippocampus, the intracerebroventricular administration of SAG (2.5 nM) significantly increases the number of newly generated cells and extends survival of hippocampal cells. ^[3] In mice, SAG (20 μg/g, i.p.) effectively prevents GC-induced neonatal cerebellar developmental abnormalities. ^[4]

Protocol (from reference)

Kinase Assay:^{^[1]}	Axl Kinase activity assay Test compounds are diluted to desired concentrations in kinase reaction buffer (50 mM HEPES pH 7.5, 10 mM MgCl², 1 mM EGTA, 2 mM DTT, and 0.01% v/v Tween-20) and are briefly incubated with Axl kinase. The Axl kinase used is recombinant human Axl kinase (catalytic domain, amino acids 473-894) with a histidine tag. The reaction is initiated by the addition of ATP and fluorescein-labeled poly-GT substrate (poly Glu:Tyr, 4:1 polymer). Concentration of the various components in the assay (10 µL reaction volume) are: 1% DMSO, 93 ng/mL Axl kinase, 20 µM ATP, and 200 nM fluorescein poly-GT substrate. Following addition of ATP and fluorescein poly-GT substrate, incubation is for 60 min at room temperature, the enzyme reaction is stopped by addition of 10 µL terbium-labeled anti-phosphotyrosine PY20 antibody in EDTA-containing buffer. Final concentration of EDTA and antibody after addition to the reaction is 10 mM and 2 nM, respectively. The terbium conjugated antibody generates a time-resolved FRET signal with the fluorescein molecule (bound to the poly-GT substrate) when the substrate is phosphorylated. After one hour incubation at room temperature, fluorescence is measured with excitation of 320 nm and dual emission of 495 and 520 nm on an EnVision microplate reader. Signal is expressed in -636996terms of a TR-FRET ratio (fluorescence intensity at 520 nm to 495 nm).
Cell Assay:^{^[1]}	Cell lines PSN-1 cells Concentrations -- Incubation Time 96 hours 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.

Kinase Assay:^{^[1]}

Axl Kinase activity assay
Test compounds are diluted to desired concentrations in kinase reaction buffer (50 mM HEPES pH 7.5, 10 mM MgCl², 1 mM EGTA, 2 mM DTT, and 0.01% v/v Tween-20) and are briefly incubated with Axl kinase. The Axl kinase used is recombinant human Axl kinase (catalytic domain, amino acids 473-894) with a histidine tag. The reaction is initiated by the addition of ATP and fluorescein-labeled poly-GT substrate (poly Glu:Tyr, 4:1 polymer). Concentration of the various components in the assay (10 µL reaction volume) are: 1% DMSO, 93 ng/mL Axl kinase, 20 µM ATP, and 200 nM fluorescein poly-GT substrate. Following addition of ATP and fluorescein poly-GT substrate, incubation is for 60 min at room temperature, the enzyme reaction is stopped by addition of 10 µL terbium-labeled anti-phosphotyrosine PY20 antibody in EDTA-containing buffer. Final concentration of EDTA and antibody after addition to the reaction is 10 mM and 2 nM, respectively. The terbium conjugated antibody generates a time-resolved FRET signal with the fluorescein molecule (bound to the poly-GT substrate) when the substrate is phosphorylated. After one hour incubation at room temperature, fluorescence is measured with excitation of 320 nm and dual emission of 495 and 520 nm on an EnVision microplate reader. Signal is expressed in -636996terms of a TR-FRET ratio (fluorescence intensity at 520 nm to 495 nm).

Cell Assay:^{^[1]}

Cell lines
PSN-1 cells
Concentrations
--
Incubation Time
96 hours
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.

References

Customer Product Validation

: Data from [Data independently produced by , , Sci Rep, 2017, 7(1):10613]

: Data from [Data independently produced by , , Cancer Cell Int, 2018, 18:63]

: Data from [Data independently produced by , , Eur J Pharmacol, 2018, 818:435-448]

Selleck's Dubermatinib(TP-0903) has been cited by 17 publications

AXL-initiated paracrine activation of pSTAT3 enhances mesenchymal and vasculogenic supportive features of tumor-associated macrophages [ Cell Rep, 2023, 42(9):113067]	PubMed: 37659081
Targeting HER2-AXL heterodimerization to overcome resistance to HER2 blockade in breast cancer [ Sci Adv, 2022, 8(20):eabk2746]	PubMed: 35594351
DETERMINING THE MECHANISMS BEHIND ADAPTIVE RESISTANCE IN FLT3/ITD AML [ Johns Hopkins University, 2022, ]	PubMed: None
Three subtypes of lung cancer fibroblasts define distinct therapeutic paradigms [ Cancer Cell, 2021, S1535-6108(21)00492-X]	PubMed: 34624218
Gas6/Axl signaling pathway promotes proliferation, migration and invasion and inhibits apoptosis in A549 cells [ Exp Ther Med, 2021, 22(5):1321]	PubMed: 34630675
Synthetic Lethal and Resistance Interactions With BET Bromodomain Inhibitors in Triple-Negative Breast Cancer [ Mol Cell, 2020, 7;S1097-2765(20)30269-0]	PubMed: 32416067
Lysosomal dysfunction and autophagy blockade contribute to autophagy-related cancer suppressing peptide-induced cytotoxic death of cervical cancer cells through the AMPK/mTOR pathway [ J Exp Clin Cancer Res, 2020, 39(1):197]	PubMed: 32962728
Single-cell Proteomic Profiling Identifies Combined AXL and JAK1 Inhibition as a Novel Therapeutic Strategy for Lung Cancer. [ Cancer Res, 2020, 10.1158/0008-5472.CAN-19-3183]	PubMed: 31992541
Targeting NAD+ biosynthesis overcomes panobinostat and bortezomib-induced malignant glioma resistance. [ Mol Cancer Res, 2020, 10.1158/1541-7786.MCR-19-0669]	PubMed: 32238439
Targeting NAD+ Biosynthesis Overcomes Panobinostat and Bortezomib-Induced Malignant Glioma Resistance [ Mol Cancer Res, 2020, 18(7):1004-1017]	PubMed: 32238439

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SHIPPING AND STORAGE
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