 Chemical Structure.png)
Physicochemical Properties
| Molecular Formula | C29H25FN4O5 |
| Molecular Weight | 528.5310 |
| Exact Mass | 528.18 |
| Elemental Analysis | C, 65.90; H, 4.77; F, 3.59; N, 10.60; O, 15.14 |
| CAS # | 2367004-54-2 |
| Related CAS # | 2367004-54-2 |
| PubChem CID | 139350422 |
| Appearance | Off-white to light brown solid powder |
| LogP | 4.7 |
| Hydrogen Bond Donor Count | 3 |
| Hydrogen Bond Acceptor Count | 7 |
| Rotatable Bond Count | 8 |
| Heavy Atom Count | 39 |
| Complexity | 885 |
| Defined Atom Stereocenter Count | 0 |
| InChi Key | JSPCKALGNNVYOO-UHFFFAOYSA-N |
| 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 |
| Synonyms | XL-092; XL092; X L092; JUN-04542; JUN04542; JUN 04542 |
| 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 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) |
Biological Activity
| 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% (mouse, 30 mg/kg), 85% (rat, 20 mg/kg), 92% (dog, 10 mg/kg) [2] - Half-life (t₁/₂): 4.2 hours (mouse), 6.8 hours (rat), 12.5 hours (dog) [2] - Cmax: 2560 ng/mL (mouse, 30 mg/kg po), 1890 ng/mL (rat, 20 mg/kg po), 1240 ng/mL (dog, 10 mg/kg po) [2] - AUC₀–24h: 8920 ng·h/mL (mouse), 9560 ng·h/mL (rat), 15600 ng·h/mL (dog) [2] - Volume of distribution (Vd): 1.8 L/kg (mouse), 2.3 L/kg (rat), 3.1 L/kg (dog) [2] - Clearance: 0.56 L/h/kg (mouse), 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 mortality observed in mice at oral dose up to 200 mg/kg [2] - Subchronic toxicity (28-day, rat): No significant changes in body weight, food intake, or hematological/biochemical parameters at doses up to 60 mg/kg/day; no organ histopathological abnormalities [2] - Cytochrome P450 inhibition: Weak inhibition of CYP3A4 (IC₅₀ = 12 μM) and no inhibition of other CYP isoforms (CYP1A2, 2C9, 2C19, 2D6) at concentrations up to 20 μM [2] |
| References |
[1]. XL092, a multi-targeted inhibitor of MET, VEGFR2, AXL and MER with an optimized pharmacokinetic profile. European Journal of Cancer, Volume 138, Supplement 2, October 2020, Page S16. [2]. Compounds for the treatment of kinase-dependent disorders. WO2019148044A1. |
| Additional Infomation |
Zanzalintinib is an orally bioavailable inhibitor of the receptor tyrosine kinases (RTKs) hepatocyte growth factor receptor (c-Met; HGFR), vascular endothelial growth factor receptor type 2 (VEGFR2), AXL and MER, with potential anti-angiogenesis and antineoplastic activities. Upon oral administration, zanzalintinib targets and binds to c-Met, VEGFR2, AXL and MER, and prevents their RTK activity. This blocks c-Met/VEGFR2/AXL/MER-mediated signal transduction pathways, and inhibits the proliferation and migration of c-Met-, VEGFR2-, AXL- and MER-overexpressing tumor cells. c-Met, overexpressed in many tumor cell types, plays a critical role in tumor formation, proliferation, invasion and metastasis, and contributes to tumor resistance. VEGFR2, overexpressed in certain tumor types, plays an essential role in angiogenesis and the proliferation, survival, migration and differentiation of endothelial cells. AXL and MER, both members of the TAM (Tyro3, Axl and Mer) family of RTKs, are overexpressed by many tumor cell types. They play key roles 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 active, multi-targeted small-molecule kinase inhibitor [1][2] - Its mechanism of action involves simultaneous inhibition of MET (tumor proliferation), VEGFR2 (angiogenesis), and AXL/MER (tumor invasion/metastasis and immune suppression) [1][2] - The compound is being developed for the treatment of kinase-dependent disorders, including MET-amplified or MET-overexpressing solid tumors [2] - Optimized pharmacokinetic profile (high oral bioavailability, long half-life) supports once-daily oral administration [1][2] - Preclinical data demonstrate synergistic antitumor activity when combined with immune checkpoint inhibitors [2] |
Solubility Data
| Solubility (In Vitro) | DMSO: 16.7~100 mg/mL (31.5~189.2 mM) |
| 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. 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. 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 corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| 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 |