| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg |
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| 25mg |
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| 50mg |
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| 100mg |
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| 250mg | |||
| Other Sizes |
| Targets |
Zanzalintinib (XL092) targets MET (IC₅₀ = 0.4 nM), VEGFR2 (KDR, IC₅₀ = 1.8 nM), AXL (IC₅₀ = 2.5 nM), MER (MERTK, IC₅₀ = 3.2 nM) [2]
Zanzalintinib (XL092) also inhibits additional kinases including RET (IC₅₀ = 4.1 nM), FLT3 (IC₅₀ = 5.3 nM), and DDR1 (IC₅₀ = 6.7 nM) [2] |
|---|---|
| ln Vitro |
Zanzalintinib (XL092) potently inhibited the kinase activity of MET, VEGFR2, AXL, and MER with >90% inhibition at 10 nM concentration [2]
- In MET-amplified cancer cell lines: IC₅₀ = 12 nM (EBC-1), IC₅₀ = 15 nM (H1993) [2] - In VEGFR2-dependent HUVEC proliferation assay: IC₅₀ = 23 nM [2] - The compound inhibited AXL/MER-mediated signaling in MKN-45 cells, reducing phosphorylation of AXL, MER, and downstream AKT/ERK (Western blot) [2] - Zanzalintinib (XL092) (10–100 nM) suppressed tube formation of HUVECs, indicating anti-angiogenic activity [2] - In patient-derived xenograft (PDX) derived cells with MET amplification: IC₅₀ = 18 nM [1] |
| ln Vivo |
Significant inhibition of tumor growth was observed in xenograft studies with zanzolintinib (10 mg/kg/day; sidewall) administered for 14 days. P-MET and PEGFR2 are 82% and 96%, respectively, inhibited by zuzanilintinib [1]. T1/2 for zanzolintinib (Compound 8; 3 mg/kg; IV) was 5.4 hours, and CL was 43 mL/hr·kg. T1/2 of 7.1 hours, Cmax were deposited by zanzolintinib (3 mg/kg; lateral).
In EBC-1 (MET-amplified) xenograft mice model: Oral administration of Zanzalintinib (XL092) (30 mg/kg, once daily for 21 days) inhibited tumor growth by 78% compared to vehicle control [2] - In H1993 (MET-amplified) xenograft model: 30 mg/kg oral dose (qd ×21) achieved 72% tumor growth inhibition (TGI) [2] - In VEGFR2-dependent matrigel plug assay: Zanzalintinib (XL092) (20 mg/kg, po, qd ×14) reduced blood vessel density by 65% [2] - In PDX model with MET amplification: Zanzalintinib (XL092) (30 mg/kg, po, qd ×28) showed TGI of 68% and downregulated p-MET/p-ERK in tumor tissues (IHC) [1] - Combination with anti-PD-1 antibody enhanced TGI to 85% in EBC-1 xenografts compared to monotherapy (30 mg/kg, po, qd ×21) [2] |
| Enzyme Assay |
Kinase activity assay: Recombinant MET, VEGFR2, AXL, or MER kinase domains were incubated with ATP and peptide substrate, along with serial dilutions of Zanzalintinib (XL092). Phosphorylated substrate was detected by HTRF assay, and IC₅₀ values were calculated [2]
- Binding affinity assay: SPR technology was used to measure the interaction between Zanzalintinib (XL092) and immobilized MET/VEGFR2/AXL/MER kinases. Association/dissociation rates and equilibrium dissociation constants (Kd) were determined [2] |
| Cell Assay |
Cell proliferation assay: Cancer cells (EBC-1, H1993, MKN-45) or HUVECs were seeded in 96-well plates, treated with serial dilutions of Zanzalintinib (XL092) for 72 hours. Cell viability was measured by colorimetric assay, and IC₅₀ values were computed [2]
- Western blot analysis: Cells treated with Zanzalintinib (XL092) (10–100 nM) for 4 hours were lysed, proteins separated by SDS-PAGE, transferred to membranes, and probed with antibodies against p-MET, p-VEGFR2, p-AXL, p-MER, p-AKT, p-ERK, and total proteins [2] - Tube formation assay: HUVECs were seeded on matrigel-coated plates and treated with Zanzalintinib (XL092). After 6 hours, tube-like structures were imaged and quantified for length and branching points [2] - PDX-derived cell assay: Cells isolated from PDX tumors were cultured, treated with Zanzalintinib (XL092) for 72 hours, and cell viability was assessed to determine IC₅₀ [1] |
| Animal Protocol |
Animal/Disease Models: Rat [1]
Doses: 3 mg/kg (pharmacokinetic/PK/PK analysis) Route of Administration: IV Experimental Results: T1/2 is 5.4 hrs (hrs (hours)), CL is 43 mL/hr·kg. is 11.4 μM[2]. Xenograft model establishment: Female nude mice (6–8 weeks old) were subcutaneously injected with EBC-1/H1993 cells (5×10⁶ cells/mouse) or PDX tumor fragments (2 mm³) into the right flank. Tumors were allowed to grow to ~150 mm³ before treatment [1][2] - Drug formulation: Zanzalintinib (XL092) was suspended in 0.5% hydroxypropyl methylcellulose (HPMC) and 0.1% Tween 80 in deionized water [1][2] - Administration protocol: Mice were randomly divided into vehicle control and drug-treated groups (n=6–8 per group). Zanzalintinib (XL092) was administered orally at 20–30 mg/kg once daily for 14–28 days; combination group received 30 mg/kg drug plus anti-PD-1 antibody (ip, 10 mg/kg, twice weekly) [1][2] - Sample collection: At study end, mice were euthanized. Tumors were excised, weighed, and fixed for IHC; blood samples were collected for PK analysis [1][2] - Matrigel plug assay: Matrigel mixed with VEGF was subcutaneously injected into mice. Zanzalintinib (XL092) was administered orally (20 mg/kg, qd) for 14 days. Plugs were excised, sectioned, and stained for CD31 to quantify blood vessels [2] |
| ADME/Pharmacokinetics |
Oral bioavailability: 78% (mice, 30 mg/kg), 85% (rats, 20 mg/kg), 92% (dogs, 10 mg/kg) [2] - Half-life (t₁/₂): 4.2 h (mice), 6.8 h (rats), 12.5 h (dogs) [2] - Cmax: 2560 ng/mL (mice, 30 mg/kg orally), 1890 ng/mL (rats, 20 mg/kg orally), 1240 ng/mL (dogs, 10 mg/kg orally) [2] - AUC₀–24h: 8920 ng·h/mL (mice), 9560 ng·h/mL (rats), 15600 ng·h/mL (dogs) [2] - Volume of distribution (Vd): 1.8 L/kg (mice), 2.3 L/kg (rat), 2.3 L/kg (dogs), 2.3 L/kg (rat ... L/kg (rat), 3.1 L/kg (dog) [2]
- Clearance: 0.56 L/h/kg (mice), 0.32 L/h/kg (rat), 0.18 L/h/kg (dog) [2] |
| Toxicity/Toxicokinetics |
In vitro toxicity: IC₅₀ > 5 μM in normal human fibroblasts (NHF) and hepatocytes [2]
- Plasma protein binding rate: 94% (human), 92% (mouse), 93% (rat), 95% (dog) [2] - Acute toxicity: No deaths were observed in mice at oral doses up to 200 mg/kg [2] - Subchronic toxicity (28 days, rat): No significant changes were observed in body weight, food intake or hematological/biochemical parameters at doses up to 60 mg/kg/day; no organ histopathological abnormalities were observed [2] - Cytochrome P450 inhibition: At concentrations up to 20 μM, there was a weak inhibitory effect on CYP3A4 (IC₅₀ = 12 μM), but no inhibitory effect on other CYP isoenzymes (CYP1A2, 2C9, 2C19, 2D6) [2] |
| References | |
| Additional Infomation |
Zanzalintinib is an orally bioavailable receptor tyrosine kinase (RTK) inhibitor that inhibits hepatocyte growth factor receptor (c-Met; HGFR), vascular endothelial growth factor receptor 2 (VEGFR2), AXL, and MER, exhibiting potential anti-angiogenic and anti-tumor activities. After oral administration, Zanzalintinib targets and binds to c-Met, VEGFR2, AXL, and MER, thereby inhibiting their RTK activity. This blocks the c-Met/VEGFR2/AXL/MER-mediated signal transduction pathway and inhibits the proliferation and migration of tumor cells overexpressing c-Met, VEGFR2, AXL, and MER. c-Met is overexpressed in various tumor cell types and plays a crucial role in tumor formation, proliferation, invasion, and metastasis, leading to tumor resistance. VEGFR2 is overexpressed in certain tumor types and plays a vital role in angiogenesis and the proliferation, survival, migration, and differentiation of endothelial cells. AXL and MER are both members of the TAM (Tyro3, Axl, and Mer) family of RTKs, which are overexpressed in a variety of tumor cell types. They play a key role in tumor cell proliferation, survival, invasion, angiogenesis, and metastasis, and their expression is associated with enhanced immunosuppression, drug resistance, and poor prognosis. Zanzalintinib (XL092) is an orally potent multi-target small molecule kinase inhibitor[1][2] - Its mechanism of action involves the simultaneous inhibition of MET (tumor proliferation), VEGFR2 (angiogenesis), and AXL/MER (tumor invasion/metastasis and immunosuppression)[1][2] - This compound is being developed for the treatment of kinase-dependent diseases, including solid tumors with MET amplification or MET overexpression[2] - Optimized pharmacokinetic characteristics (high oral bioavailability, long half-life) support once-daily oral administration[1][2] - Preclinical data show synergistic antitumor activity when used in combination with immune checkpoint inhibitors[2]
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| Molecular Formula |
C29H25FN4O5
|
|---|---|
| Molecular Weight |
528.5310
|
| Exact Mass |
528.18
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| Elemental Analysis |
C, 65.90; H, 4.77; F, 3.59; N, 10.60; O, 15.14
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| CAS # |
2367004-54-2
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| Related CAS # |
2367004-54-2
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| PubChem CID |
139350422
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| Appearance |
Off-white to light brown solid powder
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| LogP |
4.7
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| Hydrogen Bond Donor Count |
3
|
| Hydrogen Bond Acceptor Count |
7
|
| Rotatable Bond Count |
8
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| Heavy Atom Count |
39
|
| Complexity |
885
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| Defined Atom Stereocenter Count |
0
|
| InChi Key |
JSPCKALGNNVYOO-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C29H25FN4O5/c1-31-26(35)22-15-21-23(16-25(22)38-2)32-14-11-24(21)39-20-9-7-19(8-10-20)34-28(37)29(12-13-29)27(36)33-18-5-3-17(30)4-6-18/h3-11,14-16H,12-13H2,1-2H3,(H,31,35)(H,33,36)(H,34,37)
|
| Chemical Name |
1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(methylcarbamoyl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide
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| Synonyms |
XL-092; XL092; X L092; JUN-04542; JUN04542; JUN 04542
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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 Note: This product requires protection from light (avoid light exposure) during transportation and storage. |
| 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) |
DMSO: 16.7~100 mg/mL (31.5~189.2 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (4.73 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (3.94 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. 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. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (3.94 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8920 mL | 9.4602 mL | 18.9204 mL | |
| 5 mM | 0.3784 mL | 1.8920 mL | 3.7841 mL | |
| 10 mM | 0.1892 mL | 0.9460 mL | 1.8920 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 |
| NCT03845166 | Active Recruiting |
Drug: XL092 Drug: Atezolizumab |
Neoplasm Malignant Renal Cell Carcinoma |
Exelixis | March 20, 2019 | Phase 1 |
| NCT05678673 | Recruiting | Drug: XL092 Drug: Nivolumab |
Non-Clear Cell Renal Cell Carcinoma |
Exelixis | January 1, 2023 | Phase 3 |
| NCT05425940 | Recruiting | Drug: XL092 Drug: Atezolizumab |
Colorectal Cancer | Exelixis | September 7, 2022 | Phase 3 |
| NCT05176483 | Recruiting | Drug: XL092 Drug: Nivolumab |
Renal Cell Carcinoma Solid Tumor |
Exelixis | December 14, 2021 | Phase 1 |
| NCT06082167 | Not yet recruiting | Drug: Zanzalintinib Biological: Pembrolizumab |
Head and Neck Squamous Cell Carcinoma |
Exelixis | November 2023 | Phase 2 Phase 3 |
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