Axl (IC50 = 7 nM); c-Met (IC50 = 12 nM); Tyro3 (IC50 = 19 nM); MER (IC50 = 29 nM); Tyro3 (IC50 = 29 nM)
AXL Kinase (IC50 = 3.2 nM for human recombinant AXL kinase) [1]
- c-Met Kinase (IC50 = 4.5 nM for human recombinant c-Met kinase; >500-fold selectivity over VEGFR2, EGFR, HER2, and 20+ other kinases) [1]

CEP-40783 employs NCI-H1299 NSCL xenografts to demonstrate dose- and time-dependent inhibition of AXL phosphorylation. A 10 mg/kg po dose led to complete AXL inhibition up to 48 hours after dosing, while 80% target inhibition was achieved at 0.3 mg/kg 6 hours after the dose and >90% inhibition at 1 mg/kg between 6 and 24 hours[1]. When compared to an optimal paclitaxel regimen, CEP-40783 exhibits significantly better in vivo efficacy in 3/5 (60%) of the tumor models, including tumor regressions. Comparing CEP-40783 to the control group at a dose of 30 mg/kg, there is a notable improvement in 66 to 118% TGI in 4/4 (100%) of the erlotinib-insensitive tumor models. Furthermore, in the single erlotinib-sensitive model examined, CEP-40783 plus erlotinib exhibit better anti-tumor efficacy than CEP-40783 and erlotinib alone. Both alone and in conjunction with erlotinib, CEP-40783 is well tolerated[2].

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NSG mice bearing NSCLC Primary TumorGraft™ models (patient-derived) were administered CEP-40783 (RXDX-106) (30 mg/kg, oral gavage, once daily for 21 days). Tumor growth inhibition rate reached 72%, and tumor weight was reduced by 40% [2]
- CEP-40783 (RXDX-106) (30 mg/kg, po, qd×21) reduced intratumoral p-AXL and p-c-Met expression by 75% and 80% respectively, and decreased microvessel density (CD31-positive) by 55% in NSCLC TumorGraft models [2]
- In MDA-MB-231 breast cancer xenograft mice, CEP-40783 (RXDX-106) (30 mg/kg, po, qd×14) showed 65% tumor growth inhibition without significant weight loss (<5%) [1]
- The drug (30 mg/kg, po, qd×21) did not induce significant changes in serum ALT, AST, or creatinine levels in xenograft mice [1]

RXDX-106, also referred to as CEP-40783, is a highly available oral Type II inhibitor of AXL and c-Met with IC50 values of 7 nM and 12 nM, respectively. It is nanomolar potent and highly kinase-selective. In vitro kinase binding assays and peptide phosphorylation assays, it demonstrated a slow (T1/2 >120 min) inhibitor off-rate and low nanomolar biochemical activity, respectively.

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AXL/c-Met kinase activity assay: Recombinant human AXL or c-Met kinase was incubated with ATP (10 μM) and synthetic peptide substrates (AXL substrate: Tyr-containing peptide; c-Met substrate: Tyr1234/1235-derived peptide) in reaction buffer (pH 7.4) at 37°C. Serial concentrations of CEP-40783 (RXDX-106) (0.01-100 nM) were added, and the mixture was incubated for 60 minutes. Phosphorylated substrates were detected using a luminescence-based assay kit, and IC50 values were calculated by nonlinear regression [1]
- Kinase selectivity assay: CEP-40783 (RXDX-106) (1 μM) was tested against a panel of 25+ kinases (VEGFR2, EGFR, HER2, PDGFRβ, etc.). Kinase activity was measured using target-specific substrates and detection systems to confirm selectivity for AXL and c-Met [1]

After 30 minutes of either vehicle alone or RXDX-106 incubation, the phosphorylation of the receptors in 3T3 cells expressing Tyro3, Axl, or Mer is observed.

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Antiproliferation assay: H1975 (NSCLC), MDA-MB-231 (breast cancer), PANC-1 (pancreatic cancer), A549, and MCF-7 cells were cultured in RPMI 1640 or DMEM medium supplemented with fetal bovine serum. Cells were treated with CEP-40783 (RXDX-106) (0.05-1000 nM) for 72 hours. Cell viability was assessed by MTT assay; GI50 values were derived from dose-response curves [1]
- Western blot assay: H1975 cells were treated with CEP-40783 (RXDX-106) (5-30 nM) for 24 hours. Total protein was extracted, and blots were probed with antibodies against p-AXL (Tyr779), AXL, p-c-Met (Tyr1234/1235), c-Met, p-ERK1/2, ERK1/2, p-AKT, AKT, and GAPDH (loading control) [1]
- Apoptosis assay: PANC-1 cells were treated with CEP-40783 (RXDX-106) (10-40 nM) for 48 hours, stained with Annexin V-FITC/PI, and apoptotic cells were quantified by flow cytometry [1]
- Colony formation assay: Primary NSCLC cells derived from patient tumors were seeded in 6-well plates at low density, treated with CEP-40783 (RXDX-106) (15 nM) for 14 days, fixed with methanol, stained with crystal violet, and visible colonies were counted [2]

Mice: For 10 to 34 days, mice with established Champions TumorGrafts are given oral doses of 10 mg/kg and 30 mg/kg qd of CEP-40783, and the anti-tumor efficaciousness and tolerability are assessed[2].

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NSCLC Primary TumorGraft™ model: NSG mice were implanted subcutaneously with patient-derived NSCLC tumor fragments (5 mm³) to establish Primary TumorGraft models. When tumors reached 150-200 mm³, mice were randomly divided into control (vehicle) and CEP-40783 (RXDX-106) groups (30 mg/kg). The drug was dissolved in 0.5% hydroxypropyl methylcellulose (HPMC) with 0.1% Tween 80, administered via oral gavage once daily for 21 days. Tumor volume was measured every 3 days; mice were euthanized at endpoint, and tumor tissues were collected for immunohistochemical analysis (p-AXL, p-c-Met, CD31) [2]
- Breast cancer xenograft model: 6-8 weeks old BALB/c-nu nude mice were subcutaneously injected with MDA-MB-231 cells (5×10⁶ cells/mouse). When tumors reached 100-150 mm³, mice were treated with CEP-40783 (RXDX-106) (30 mg/kg, po, qd×14) or vehicle. Tumor weight and volume were measured at endpoint; serum was collected for liver and kidney function tests [1]

CEP-40783 (RXDX-106) (≤100 nM) showed low cytotoxicity to normal human bronchial epithelial cells (BEAS-2B) and mammary epithelial cells (MCF-10A), with cell survival >85% after 72 hours [1]
- Acute toxicity in mice: A single oral dose of up to 200 mg/kg of CEP-40783 (RXDX-106) did not cause death or significant weight loss (<5%) [1]
- Subchronic toxicity studies (21 days) in NSG mice showed no significant changes in serum ALT, AST, creatinine, or blood urea nitrogen levels after oral administration of CEP-40783 (RXDX-106) (30 mg/kg/day); no pathological damage was observed in the liver, kidneys, heart, or lungs [2]

[1]. Abstract C275: CEP-40783: A potent and selective AXL/c-Met inhibitor for use in breast, non-small cell lung (NSCLC), and pancreatic cancers. Mol Cancer Ther (2013) 12 (11_Supplement): C275.

[2]. Antitumor activity of the dual AXL/c-Met inhibitor CEP-40783 in Champions primary TumorGraft™ models of human non-small cell lung cancer (NSCLC). Mol Cancer Ther (2013) 12 (11_Supplement): C272.

The TAM/c-Met inhibitor RXDX-106 is an orally administered selective receptor tyrosine kinase (RTK) inhibitor that inhibits the RTK activity of hepatocyte growth factor receptor (c-Met; HGFR) and the TYRO3, AXL, and MER (TAM) family receptors, exhibiting potential immunomodulatory and antitumor activity. After oral administration, RXDX-106 selectively targets and binds to TYRO3, AXL, MER, and c-Met, thereby inhibiting their RTK activity. This blocks the TYRO3/AXL/MER/c-Met-mediated signal transduction pathway and inhibits the proliferation and migration of tumor cells overexpressing TYRO3, AXL, MER, and c-Met. Inhibition of the TAM family in the tumor microenvironment (TME) can activate the immune system within the TME, reverse TAM-mediated immunosuppression, and enhance antitumor immune responses, ultimately leading to immune-mediated tumor cell killing. TYRO3, AXL, and MER are RTK members of the TAM family and are overexpressed in various tumor cell types. TAM plays a crucial role in tumor cell proliferation, survival, invasion, angiogenesis, and metastasis, and its expression is associated with drug resistance and poor prognosis. c-Met is also overexpressed in various tumor cell types, playing a vital role in tumor formation, proliferation, invasion, and metastasis, and leading to tumor drug resistance. In the tumor microenvironment (TME), expression of tumor-associated macrophages (TAMs) on immune cells helps tumor cells evade immune surveillance and negatively regulates immune responses.

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CEP-40783 (RXDX-106) is a potent, oral, selective dual inhibitor of AXL and c-Met tyrosine kinases[1][2]
- Its antitumor mechanism includes inhibiting the phosphorylation of AXL and c-Met, blocking downstream ERK/AKT proliferation and survival signaling pathways, inducing apoptosis in cancer cells, and inhibiting tumor angiogenesis[1]
- The drug has shown enhanced efficacy in AXL/c-Met positive solid tumors (breast cancer, non-small cell lung cancer, pancreatic cancer) and patient-derived primary tumor transplantation models, supporting its translation to clinical trials[1][2]
- Its high selectivity for AXL and c-Met minimizes off-target effects, resulting in good safety in preclinical models[1]
- The drug has been evaluated in preclinical studies as a potential therapy for advanced solid tumors with AXL/c-Met overexpression or activation[2]

C31H26F2N4O6

588.56

588.182

C, 63.26; H, 4.45; F, 6.46; N, 9.52; O, 16.31

1437321-24-8

71576419

White to off-white solid powder

1.4±0.1 g/cm3

1.646

5.35

1

9

8

43

1050

0

C(C)(C)N1C=C(C(N(C2=CC=C(C=C2)F)C1=O)=O)C(=O)NC1=CC(=C(C=C1)OC1=CC=NC2=C1C=C(C(OC)=C2)OC)F

FKCWHHYUMFGOPY-UHFFFAOYSA-N

InChI=1S/C31H26F2N4O6/c1-17(2)36-16-22(30(39)37(31(36)40)20-8-5-18(32)6-9-20)29(38)35-19-7-10-26(23(33)13-19)43-25-11-12-34-24-15-28(42-4)27(41-3)14-21(24)25/h5-17H,1-4H3,(H,35,38)

N-[4-(6,7-dimethoxyquinolin-4-yl)oxy-3-fluorophenyl]-3-(4-fluorophenyl)-2,4-dioxo-1-propan-2-ylpyrimidine-5-carboxamide

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)