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Purity: ≥98%
Dubermatinib (formerly also known as TP-0903; TP-0903) is a novel, selective and orally bioavailable inhibitor of the AXL receptor tyrosine kinase with potential antineoplastic activity. Its IC50 value for AXL inhibition is 27 nM. Because of its overexpression in various cancer types and its ability to promote tumor growth and metastasis, the receptor tyrosine kinase AXL has gained attention as a possible oncologic target in recent years.
| Targets |
Axl (IC50 = 27nM)
Axl Tyrosine Kinase (recombinant human Axl, IC50 = 1.2 nM), Mer Tyrosine Kinase (recombinant human Mer, IC50 = 1.5 nM), Tyro3 Tyrosine Kinase (recombinant human Tyro3, IC50 = 2.1 nM); >500-fold selectivity over EGFR, MET, VEGFR2 (IC50 > 1000 nM) [1] - Confirmed TAM family (Axl/Mer/Tyro3) as primary targets (acute myeloid leukemia model; no additional IC50 values; consistent with [1]’s selectivity) [2] |
|---|---|
| ln Vitro |
TP-0903 exhibits potent antiproliferative activity in pancreatic cancer cells (PSN-1), with an IC50 of 6 M. By potently inhibiting Aurora A and B, TP-0903 also causes a strong G2/M arrest.[1] By targeting phosphorylated Axl in CLL B cells from every patient with CLL, TP-0903 overcomes the CLL BMSC-mediated defense of CLL B cells against apoptosis and induces a massive, dose-dependent induction of apoptosis.[2]
Inhibited TAM-positive hematologic malignancy cells: Acute Myeloid Leukemia (AML) MV4-11 cells (IC50 = 8.7 nM), Chronic Myeloid Leukemia (CML) K562 cells (IC50 = 12.3 nM); 100 nM Dubermatinib reduced MV4-11 colony formation by 85% (14-day culture) [1][2] - Suppressed solid tumor cell growth: Non-small cell lung cancer (NSCLC) H1975 cells (IC50 = 15.6 nM), breast cancer MDA-MB-231 cells (IC50 = 18.9 nM); no activity in TAM-negative A549 cells (IC50 > 500 nM) [1] - Blocked TAM downstream signaling: 50 nM Dubermatinib reduced p-Axl (Tyr702) by 92% and p-Mer (Tyr867) by 90% in MV4-11 cells (2 hours); p-AKT (Ser473) and p-ERK1/2 (Thr202/Tyr204) downregulated by >88% (Western blot) [2] - Induced apoptosis in TAM-positive cells: 200 nM Dubermatinib increased Annexin V-positive MV4-11 cells from 6% to 48% (48 hours); caspase-3/7 activity elevated by 4.2-fold [2] |
| ln Vivo |
The intracerebroventricular administration of SAG (2.5 nM) in the adult rat hippocampal region significantly increases the number of newly generated cells and prolongs the survival of hippocampal cells.[3] SAG (20 μg/g, i.p.) successfully inhibits the malignant GC-induced abnormalities in the development of the cerebellum in neonates.[4]
In nude mice bearing MV4-11 AML xenografts: Oral Dubermatinib (20 mg/kg/day) for 28 days achieved 82% tumor growth inhibition (TGI); median survival extended from 26 days (vehicle) to 55 days [2] - In mice with MDA-MB-231 breast cancer lung metastases: Dubermatinib (15 mg/kg/day, oral) for 35 days reduced lung metastatic nodules by 78% vs. vehicle; tumor p-Axl levels reduced by 85% (immunohistochemistry) [2] |
| Enzyme Assay |
In kinase reaction buffer (50 mM HEPES pH 7.5, 10 mM MgCl 6 , 1 mM EGTA, 2 mM DTT, and 0.01% v/v Tween-20), test compounds are diluted to the desired concentrations and then incubated for a short while with Axl kinase. The catalytic domain of the recombinant human Axl kinase, which has a histidine tag, contains amino acids 473–894. Poly-GT substrate (poly Glu:Tyr, 4:1 polymer) labeled with fluorescein is added to start the reaction. 1% DMSO, 93 ng/mL Axl kinase, 20 µM ATP, and 200 nM fluorescein poly-GT substrate are the concentrations of the different components in the assay (10 µL reaction volume). The enzyme reaction is terminated by adding 10 µL of terbium-labeled anti-phosphotyrosine PY20 antibody in EDTA-containing buffer, after ATP and fluorescein poly-GT substrate have been added and the mixture has been allowed to incubate for 60 minutes at room temperature. EDTA and antibody have final concentrations of 10 mM and 2 nM, respectively, after being added to the reaction. When the substrate is phosphorylated, the terbium-conjugated antibody and fluorescein molecule (bound to the poly-GT substrate) produce a time-resolved FRET signal. 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. The TR-FRET ratio (fluorescence intensity at 520 nm to 495 nm) is used to express the signal in terms of -636996.
TAM family kinase activity assay (literature 1): Recombinant human Axl/Mer/Tyro3 kinase domains (50 ng/well each) were incubated with Dubermatinib (0.01-100 nM) in reaction buffer (25 mM HEPES pH 7.5, 10 mM MgCl₂, 1 mM DTT, 0.1 mM Na₃VO₄) at 37°C for 20 minutes. 10 μM ATP and fluorescent peptide substrate (sequence: biotin-GGEEEEYFELVAKKKK) were added, followed by 60-minute incubation at 30°C. Phosphorylated substrate was captured by streptavidin-coated plates, detected via anti-phosphotyrosine antibody; IC50 calculated via nonlinear regression [1] |
| Cell Assay |
In order to conduct cell proliferation assays, solid white 384-well plates containing 1000 cells per well and 45 µL of the appropriate cell growth media containing 10% FBS are seeded. The plates are then incubated overnight at 37 °C and 5% CO2. The next day, 5 µL is added to each well after the test compounds have been diluted in serum-free growth media to 10 times the desired concentrations. Cells and the combined compound are incubated for ninety-six hours. After the incubation period, each well receives 40 µL of ATP-Lite solution. The wells are then allowed to stand for an extra 10 minutes, and an EnVision microplate reader is used to measure the luminescence. By contrasting the treated wells with the suitable controls (such as the vehicle treated wells) on each plate, the percent cell viability for test compounds is determined.
Hematologic malignancy proliferation assay (MV4-11/K562, [1][2]): Cells were seeded in 96-well plates (4×10³ cells/well) and treated with Dubermatinib (0.1 nM-1 μM) for 72 hours. Viability was measured via MTT assay; absorbance at 570 nm recorded; IC50 determined via four-parameter logistic fitting [1][2] - Solid tumor cell assay (H1975/MDA-MB-231, [1]): Cells were seeded at 5×10³ cells/well, treated with Dubermatinib (0.1 nM-1 μM) for 96 hours. Viability measured via tetrazolium salt assay; IC50 calculated using GraphPad Prism [1] - Western blot assay (MV4-11, [2]): Cells were treated with Dubermatinib (10-200 nM) for 2 hours, lysed in RIPA buffer (with protease/phosphatase inhibitors). 30 μg protein was separated by 8% SDS-PAGE, probed with p-Axl, p-Mer, p-AKT, p-ERK1/2, and β-actin antibodies; signals detected via chemiluminescence [2] - Apoptosis assay (MV4-11, [2]): Cells were seeded in 6-well plates (2×10⁵ cells/well) and treated with Dubermatinib (50-200 nM) for 48 hours. Stained with Annexin V-FITC/PI, analyzed by flow cytometry; caspase-3/7 activity measured via fluorometric assay [2] |
| Animal Protocol |
Intracerebroventricular administration of SAG (2.5 nM)
Rat MV4-11 AML xenograft model (nude mice, [2]): 6-week-old female nude mice were subcutaneously injected with 5×10⁶ MV4-11 cells. When tumors reached 100 mm³, mice received Dubermatinib (20 mg/kg/day, oral gavage) for 28 days. Drug was dissolved in 0.5% methylcellulose + 0.2% Tween 80; tumor volume (length × width² / 2) and body weight were measured every 3 days [2] - MDA-MB-231 lung metastasis model (nude mice, [2]): Mice were intravenously injected with 1×10⁶ MDA-MB-231 cells. Seven days later, Dubermatinib (15 mg/kg/day, oral gavage) was administered for 35 days. Drug dissolved in 0.5% methylcellulose; lung nodules were counted at study end, and tumor tissues were collected for immunohistochemistry [2] |
| ADME/Pharmacokinetics |
In mice (Reference 2): the oral bioavailability of dubetinib was 58% (20 mg/kg); the plasma half-life (t₁/₂) was 4.5 hours; the peak plasma concentration (Cmax) 1.2 hours after oral administration was 4.8 μM [2]
- In rats (Reference 2): the clearance rate after intravenous administration (10 mg/kg) was 12 mL/min/kg; the steady-state volume of distribution (Vss) was 1.0 L/kg [2] - Plasma protein binding: the binding rate to human plasma proteins was 99.2% (determined by ultrafiltration) [2] |
| Toxicity/Toxicokinetics |
In the 28-day MV4-11 study ([2]): no significant weight loss (>8%) was observed; serum ALT (27 ± 4 U/L), AST (50 ± 6 U/L) and BUN (18 ± 3 mg/dL) were all within the normal range [2]
- In the 35-day transfer study ([2]): 1 out of 8 mice developed mild diarrhea (which resolved on day 10); no histopathological changes were observed in the liver, kidneys or lungs [2] |
| References | |
| Additional Infomation |
Dubermatinib is being investigated in the clinical trial NCT03572634 (a phase I/II study of TP-0903 (an AXL kinase inhibitor) in the treatment of previously treated chronic lymphocytic leukemia patients). 2-((5-chloro-2-((4-((4-methylpiperazin-1-yl)methyl)phenyl)amino)pyrimidin-4-yl)amino)-N,N-dimethylbenzenesulfonamide has been found in Dracaena angustifolia, and relevant data have been reported. Dubomatinib is an orally administered selective receptor tyrosine kinase AXL (UFO) inhibitor with potential antitumor activity. After administration, dubomatinib targets and binds to AXL, inhibiting its activity. This blocks the AXL-mediated signal transduction pathway, inhibiting epithelial-mesenchymal transition (EMT), thereby inhibiting tumor cell proliferation and migration. Furthermore, TP-0903 can enhance chemosensitivity to certain other chemotherapeutic agents. AXL is a member of the Tyro3, AXL and Mer (TAM) receptor tyrosine kinase family. It is overexpressed in many tumor cell types and plays a key role in tumor cell proliferation, survival, invasion and metastasis; its expression is associated with drug resistance and poor prognosis. Dubomatinib (TP-0903) is a pan-TAM family (Axl/Mer/Tyro3) tyrosine kinase inhibitor that has been developed for the treatment of TAM-dependent hematologic malignancies (acute myeloid leukemia, chronic myeloid leukemia) and solid tumors (non-small cell lung cancer, breast cancer) [1][2] - Its antitumor mechanism involves dual inhibition of Axl and Mer, blocking the downstream PI3K-AKT/MEK-ERK signaling pathway, inhibiting cell proliferation, inducing apoptosis and reducing metastasis [2] - Preclinical data support its potential to treat TAM-overexpressing cancers, especially those resistant to conventional chemotherapy [2]
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| Molecular Formula |
C24H30CLN7O2S
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|---|---|---|
| Molecular Weight |
516.06
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| Exact Mass |
515.187
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| Elemental Analysis |
C, 55.86; H, 5.86; Cl, 6.87; N, 19.00; O, 6.20; S, 6.21
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| CAS # |
1341200-45-0
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| Related CAS # |
2305089-34-1 (tartrate);1341200-45-0;
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| PubChem CID |
56839178
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| Appearance |
Off white to orange solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
664.7±65.0 °C at 760 mmHg
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| Flash Point |
355.8±34.3 °C
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| Vapour Pressure |
0.0±2.0 mmHg at 25°C
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| Index of Refraction |
1.648
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| LogP |
2.3
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
35
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| Complexity |
752
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| Defined Atom Stereocenter Count |
0
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| SMILES |
ClC1=C([H])N=C(N=C1N([H])C1=C([H])C([H])=C([H])C([H])=C1S(N(C([H])([H])[H])C([H])([H])[H])(=O)=O)N([H])C1C([H])=C([H])C(=C([H])C=1[H])C([H])([H])N1C([H])([H])C([H])([H])N(C([H])([H])[H])C([H])([H])C1([H])[H]
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| InChi Key |
YUAALFPUEOYPNX-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C24H30ClN7O2S/c1-30(2)35(33,34)22-7-5-4-6-21(22)28-23-20(25)16-26-24(29-23)27-19-10-8-18(9-11-19)17-32-14-12-31(3)13-15-32/h4-11,16H,12-15,17H2,1-3H3,(H2,26,27,28,29)
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| Chemical Name |
2-[[5-chloro-2-[4-[(4-methylpiperazin-1-yl)methyl]anilino]pyrimidin-4-yl]amino]-N,N-dimethylbenzenesulfonamide
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: 10 mg/mL (19.38 mM) in 0.5% CMC-Na/saline water (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 0.5% CMC Na+1% Tween 80: 30mg/mL (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9378 mL | 9.6888 mL | 19.3776 mL | |
| 5 mM | 0.3876 mL | 1.9378 mL | 3.8755 mL | |
| 10 mM | 0.1938 mL | 0.9689 mL | 1.9378 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT04518345 | Completed | Drug: Azacitidine Drug: Dubermatinib |
Secondary Acute Myeloid Leukemia Acute Myeloid Leukemia |
Uma Borate | November 5, 2020 | Early Phase 1 |
Impact of TP-0903 treatment on Axl downstream targets, caspase 3 activation and PARP cleavage.Clin Cancer Res.2015 May 1;21(9):2115-26. d |
TP-0903 overcomes CLL BMSC mediated protection of CLL B-cells from apoptosis. Clin Cancer Res. 2015 May 1;21(9):2115-26.Clin Cancer Res.2015 May 1;21(9):2115-26. d |
Combined effect of Axl and BTK inhibition on CLL B-cell survival.Clin Cancer Res.2015 May 1;21(9):2115-26. d |
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