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RXDX-106 (also known as CEP-40783) is an orally bioavailable, nanomolar potent and highly kinase-selective Type II inhibitor of AXL and c-Met with IC50 values of 7 nM and 12 nM, respectively. In assays for peptide phosphorylation and in vitro kinase binding, it demonstrated low nanomolar biochemical activity and a slow (T1/2 >120 min) inhibitor off-rate, respectively. In comparison to SOC agents, CEP-40783 exhibits greater efficacy both by itself and in conjunction with erlotinib in Champions TumorGraft™ models of NSCLC, which encourages the development of CEP-40783 for the treatment of erlotinib-resistant NSCLC.
Physicochemical Properties
| Molecular Formula | C31H26F2N4O6 | |
| Molecular Weight | 588.56 | |
| Exact Mass | 588.182 | |
| Elemental Analysis | C, 63.26; H, 4.45; F, 6.46; N, 9.52; O, 16.31 | |
| CAS # | 1437321-24-8 | |
| Related CAS # |
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| PubChem CID | 71576419 | |
| Appearance | White to off-white solid powder | |
| Density | 1.4±0.1 g/cm3 | |
| Index of Refraction | 1.646 | |
| LogP | 5.35 | |
| Hydrogen Bond Donor Count | 1 | |
| Hydrogen Bond Acceptor Count | 9 | |
| Rotatable Bond Count | 8 | |
| Heavy Atom Count | 43 | |
| Complexity | 1050 | |
| Defined Atom Stereocenter Count | 0 | |
| SMILES | 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 |
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| InChi Key | FKCWHHYUMFGOPY-UHFFFAOYSA-N | |
| InChi Code | 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) | |
| Chemical Name | N-[4-(6,7-dimethoxyquinolin-4-yl)oxy-3-fluorophenyl]-3-(4-fluorophenyl)-2,4-dioxo-1-propan-2-ylpyrimidine-5-carboxamide | |
| Synonyms |
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| HS Tariff Code | 2934.99.9001 | |
| 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) |
Biological Activity
| Targets |
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] |
| ln Vitro |
CEP-40783 has an IC50 value of 0.26 nM, which is 27-fold more active than recombinant enzyme in AXL-transfected 293GT cells. Additionally, CEP-40783 exhibits superior activity (IC50=6 nM) against c-Met in GTL-16 cells. CEP-40783's longer residence time on both AXL and c-Met may have contributed to its increased inhibitory activity in cells, which is in line with a Type II mechanism. Against 298 kinases, CEP-40783 exhibits strong kinome selectivity with an S90 of 0.04 (the fraction of kinases demonstrating >90% inhibition at 1 µM)[1]. CEP-40783 (RXDX-106) (0.1-100 nM) dose-dependently inhibited kinase activity of recombinant human AXL and c-Met, with 90% inhibition at 20 nM for both targets [1] - The drug selectively suppressed proliferation of AXL/c-Met-positive cancer cell lines: GI50 = 15 nM (H1975 NSCLC), GI50 = 18 nM (MDA-MB-231 breast cancer), GI50 = 22 nM (PANC-1 pancreatic cancer) after 72 hours; GI50 > 500 nM in AXL/c-Met-low expressing cells (A549, MCF-7) [1] - CEP-40783 (RXDX-106) (10 nM) reduced phosphorylation of AXL (Tyr779) by 78% and c-Met (Tyr1234/1235) by 82% in H1975 cells, inhibiting downstream ERK1/2 and AKT phosphorylation by 65% and 70% respectively [1] - CEP-40783 (RXDX-106) (20 nM) induced apoptotic rate of 38% in PANC-1 cells after 48 hours, as detected by Annexin V-FITC/PI staining [1] - In NSCLC primary tumor-derived cell lines (n=5), CEP-40783 (RXDX-106) (15 nM) inhibited colony formation by 62% compared to vehicle controls [2] |
| ln Vivo |
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]. 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] |
| Enzyme Assay |
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. 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] |
| Cell Assay |
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. 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] |
| Animal Protocol |
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]. 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] |
| Toxicity/Toxicokinetics |
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 viability >85% after 72 hours [1] - Acute toxicity in mice: Single oral administration of CEP-40783 (RXDX-106) up to 200 mg/kg did not cause mortality or significant weight loss (<5%) [1] - Subchronic toxicity study (21 days) in NSG mice administered CEP-40783 (RXDX-106) (30 mg/kg/day, po) showed no significant changes in serum ALT, AST, creatinine, or blood urea nitrogen levels; no pathological damage was observed in liver, kidney, heart, or lung [2] |
| References |
[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. |
| Additional Infomation |
TAM/c-Met Inhibitor RXDX-106 is an orally available and selective inhibitor of the receptor tyrosine kinase (RTK) activity of both hepatocyte growth factor receptor (c-Met; HGFR) and receptors in the TYRO3, AXL, and MER (TAM) family, with potential immunomodulating and antineoplastic activities. Upon oral administration of TAM/c-Met inhibitor RXDX-106, this agent selectively targets and binds to TYRO3, AXL, MER and c-Met, and prevents their RTK activity. This blocks TYRO3/AXL/MER/c-Met-mediated signal transduction pathways, and inhibits the proliferation and migration of TYRO3-, AXL-, MER- and c-Met-overexpressing tumor cells. Inhibition of the TAM family in the tumor microenvironment (TME) activates the immune system in the TME, reverses TAM mediated immunosuppression and enhances the anti-tumor immune response, which lead to immune-mediated tumor cell killing. TYRO3, AXL and MER, members of the TAM family of RTKs, are overexpressed in many tumor cell types. TAMs play key roles in tumor cell proliferation, survival, invasion, angiogenesis and metastasis, and their expression is associated with drug resistance and poor prognosis. c-Met, also overexpressed in many tumor cell types, plays a critical role in tumor formation, proliferation, invasion and metastasis, and contributes to tumor resistance. In the TME, TAM expression on immune cells contributes to tumor cell evasion of immune surveillance and to the negative regulation of immune responses. CEP-40783 (RXDX-106) is a potent, oral, selective dual inhibitor of AXL and c-Met tyrosine kinases [1][2] - Its anti-tumor mechanism involves inhibiting AXL and c-Met phosphorylation, blocking downstream ERK/AKT proliferative and survival signaling pathways, inducing cancer cell apoptosis, and suppressing tumor angiogenesis [1] - The drug exhibits enhanced efficacy in AXL/c-Met-positive solid tumors (breast cancer, NSCLC, pancreatic cancer) and patient-derived Primary TumorGraft models, supporting its translation to clinical trials [1][2] - High selectivity for AXL and c-Met minimizes off-target effects, contributing to its favorable safety profile in preclinical models [1] - The drug was evaluated in preclinical studies as a potential therapy for advanced solid tumors with AXL/c-Met overexpression or activation [2] |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
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. Injection Formulations (e.g. IP/IV/IM/SC) 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). 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) Oral Formulations 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). 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 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.6991 mL | 8.4953 mL | 16.9906 mL | |
| 5 mM | 0.3398 mL | 1.6991 mL | 3.3981 mL | |
| 10 mM | 0.1699 mL | 0.8495 mL | 1.6991 mL |