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Bozitinib (Vebreltinib; formerly APL-101/PLB-1001, CBT-101) is a novel, an ATP-competitive, and highly selective c-MET kinase inhibitor with blood-brain barrier permeability. Bozitinib (PLB-1001) attaches itself to the tyrosine kinase superfamily's typical ATP-binding pocket. Phase I/II trials are presently investigating it as a single agent in patients with solid tumors, non-small cell lung cancer (NSCLC), and glioblastomas; additionally, it is being investigated in patients with hepatocellular carcinoma and renal cell carcinoma in combination with PD-L1 inhibitors. Due to its ability to cross the blood–brain barrier, the medication has shown promise in treating glioblastoma and has shown anticancer effects in a number of human xenograft tumor models with MET dysregulation. A small number of patients with chemotherapy-resistant, MET-altered gliomas have shown the drug's safety and preliminary efficacy. In China, a phase II trial (NCT04258033) is assessing bozitinib in patients with non-small cell lung cancer (NSCLC) who have skipped MET exon 14.
Vebreltinib is an orally bioavailable inhibitor of the proto-oncogene c-Met (hepatocyte growth factor receptor; HGFR) with potential antineoplastic activity. Upon administration, it selectively binds to c-Met, thereby inhibiting c-Met phosphorylation and disrupting c-Met signal transduction pathways. This may induce cell death in tumor cells that overexpress or harbor constitutively activated c-Met protein. c-Met, a receptor tyrosine kinase overexpressed or mutated in many tumor types, plays key roles in tumor cell proliferation, survival, invasion, metastasis, and tumor angiogenesis.| Targets |
c-Met
The phosphorylation of MET and STAT3 is inhibited by bozitinib (PLB-1001) (30 μM; 6 hours), and PLB-1001 has more inhibitory effects on MET and its downstream signaling buffers. |
|---|---|
| ln Vitro |
The phosphorylation of MET and STAT3 is inhibited by bozitinib (PLB-1001) (30 μM; 6 hours), and PLB-1001 has more inhibitory effects on MET and its downstream signaling buffers.
PLB-1001 treatment (30 nM, 6 hr) inhibited phosphorylation of MET (Y1234/Y1235) and its downstream effector STAT3 (Y705) in human astrocytes transiently overexpressing ZM fusion variants (E1-E2 or E2-E2), METex14, or wild-type MET, as demonstrated by Western blotting. This inhibitory effect was comparable to that of crizotinib (3 µM, 6 hr). [1] In a drug sensitivity assay, four MET inhibitors (including PLB-1001) demonstrated significantly better growth inhibition effects (lower normalized Area Under the Curve, AUC) on a ZM fusion-positive patient-derived glioma cell line and a METex14-positive patient-derived cell line compared to 56 non-MET inhibitors. [1] |
| ln Vivo |
In subcutaneous xenograft models using U87 MG cells stably expressing the ZM E2-E2 fusion, daily oral administration of PLB-1001 (100 mg/kg/day) significantly reduced tumor growth and final tumor weight compared to vehicle or crizotinib (50 mg/kg/day) treatment. [1]
In an intracranial orthotopic xenograft model with ZM E2-E2-expressing U87 MG cells, PLB-1001 treatment (50 mg/kg/day, oral gavage) initiated 14 days post-implantation suppressed tumor growth as assessed by MRI at 30 days. Withdrawal of the drug led to resumed tumor growth. PLB-1001 treatment significantly prolonged overall survival of mice compared to the vehicle-treated group. Immunohistochemical analysis of tumors from treated mice showed diminished staining intensities of p-MET, p-STAT3, Ki-67, CD31, and pHH3. [1] |
| Enzyme Assay |
The selectivity of PLB-1001 for MET kinase was assessed using a LANCE enzyme assay. The inhibition rate of 100 different kinases was tested by detecting the level of ULight/CREBtide-substrate phosphorylation after incubation with 2 µM of PLB-1001. MET kinase activity was inhibited by 95.1%, while other kinases were barely inhibited. The list of assayed kinases is provided in the supplementary table of the literature. [1]
|
| Cell Assay |
Western Blot analysis [1]
Cell Types: human astrocytes (HA) Cell Tested Concentrations: 30 μM Incubation Duration: 6 hrs (hours) Experimental Results: p-STAT3, p-MET expression diminished. For cell viability assays, cells were seeded in 96-well plates. Cell viability was assessed daily over 6 days using an MTS assay according to the standard protocol. [1] For drug sensitivity analysis in patient-derived cells (PDCs), cells were seeded in 384-well plates and treated with a seven-point serial dilution series of drugs. After 6 days of treatment, cell viability was analyzed using an ATP-monitoring system. Dose-response curves were fitted, and the Area Under the Curve (AUC) was calculated for evaluation. [1] Western blotting was performed to analyze protein expression and phosphorylation. Tissue or cell lysates were prepared, and equal amounts of total protein were separated by SDS/PAGE, transferred to PVDF membranes, and detected using an ECL system. Beta-Tubulin or GAPDH was used as a loading control. [1] Immunohistochemical staining was performed on paraffin-embedded tissue sections. After deparaffinization, rehydration, and antigen retrieval, sections were incubated with primary antibodies overnight at 4°C, followed by incubation with secondary antibodies and 3,3'-diaminobenzidine staining. [1] |
| Animal Protocol |
For subcutaneous xenograft studies, U87 MG cells transduced with ZM E2-E2 fusion or control vector were injected subcutaneously into the flank of female BALB/c nude mice. When tumors reached approximately 100 mm³, mice were randomized to receive daily oral gavage of PLB-1001 (100 mg/kg), crizotinib (50 mg/kg), or vehicle (0.9% normal saline). Tumor dimensions were measured periodically, and volumes were calculated. [1]
For intracranial orthotopic models, U87 MG cells expressing ZM E2-E2 fusion were implanted into the brains of female BALB/c nude mice using a stereotactic apparatus. Tumor growth was monitored by MRI. Mice with established tumors (∼80 mm³) were treated daily with PLB-1001 (50 mg/kg, oral gavage) or vehicle. [1] For pharmacokinetic studies in rats, Sprague-Dawley rats were fasted for 16 hours before intragastric administration of PLB-1001 at 4.5 mg/kg body weight. Blood and brain tissue were collected at specified time points post-administration for drug concentration analysis. [1] |
| ADME/Pharmacokinetics |
In the MDCK-MDR1 cell permeability assay, PLB-1001 showed higher apparent permeability and lower excretion rate compared to other MET inhibitors (crizotinib, cabozantinib, faritinib) and temozolomide. The excretion rate of PLB-1001 was similar to that of non-substrate P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), indicating that it is not a substrate of these major blood-brain barrier efflux transporters. [1]
After gavage administration of 4.5 mg/kg PLB-1001 to Sprague-Dawley rats, the drug concentration in brain tissue reached a peak of 0.207 µg/g tissue weight (brain/plasma ratio of approximately 1.75%) at 3 hours and then gradually decreased. [1] In a phase I clinical trial, plasma concentrations of PLB-1001 remained stable between 1000 and 6000 ng/mL within 24 hours after a single oral dose in glioma patients. The concentration of PLB-1001 in the cerebrospinal fluid (CSF) collected on day 15 was approximately 3% to 8% of the plasma concentration at the same time. [1] |
| Toxicity/Toxicokinetics |
In a phase I clinical trial involving 18 patients with recurrent high-grade gliomas, no cases of DLT or death related to PLB-1001 were observed during the 4-week dose-limiting toxicity (DLT) observation period. The maximum tolerated dose (MTD) was not reached. [1] Grade 3 hepatotoxic adverse events (AEs) were observed in two patients with grade III gliomas: one patient (200 mg twice daily) experienced an increase in alanine aminotransferase (ALT) at week 12, and the other patient (300 mg twice daily) experienced an increase in total bilirubin at week 7. Neither of these adverse events occurred during the DLT observation period. Common grade 1-2 adverse events included increases in serum lipase and aspartate aminotransferase and decreases in albumin. [1]
|
| References | |
| Additional Infomation |
Vebreltinib is an orally bioavailable proto-oncogene c-Met (hepatocyte growth factor receptor; HGFR) inhibitor with potential antitumor activity. After administration, Vebreltinib selectively binds to c-Met, thereby inhibiting c-Met phosphorylation and disrupting the c-Met signaling pathway. This may induce death in tumor cells that overexpress or constitutively activate c-Met protein. c-Met is a receptor tyrosine kinase that is overexpressed or mutated in various tumor cell types and plays a crucial role in tumor cell proliferation, survival, invasion, metastasis, and tumor angiogenesis.
Bozitinib (PLB-1001) is also known as CBI-3103 or IDD-100. Its chemical name is (6-(1-cyclopropyl-1H-pyrazole-4-yl)-3-[difluoro(6-fluoro-2-methyl-2H-indazole-5-yl)methyl]-[1,2,4]triazolo[4,3-b]pyridazine). [1] Molecular dynamics simulations suggest that PLB-1001 has additional interacting sites within the MET kinase ATP binding pocket compared to crizotinib, which may contribute to improved binding affinity and specificity. [1] The drug was evaluated in a phase I, open-label, 3+3 dose-escalation study (NCT02978261) in patients with recurrent high-grade gliomas carrying the ZM fusion gene and/or METex14. The recommended dose (RP2D) for monotherapy in phase II was determined to be 300 mg twice daily. [1] Among evaluable patients, 2 out of 6 sGBM patients achieved partial remission (PR), 2 out of 6 sGBM patients and 5 out of 9 grade III glioma patients achieved stable disease (SD) according to RANO criteria. [1] Analysis of recurrent tumors in a patient who initially responded to PLB-1001 but later progressed revealed acquired mutations in PI3K-Akt-mTOR pathway genes (PIK3CA, PIK3CG, PTEN), suggesting a possible resistance mechanism to MET inhibitor monotherapy. [1] |
| Molecular Formula |
C20H15F3N8
|
|---|---|
| Molecular Weight |
424.381912469864
|
| Exact Mass |
424.14
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| Elemental Analysis |
C, 56.60; H, 3.56; F, 13.43; N, 26.40
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| CAS # |
1440964-89-5
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| Related CAS # |
1440964-89-5
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| PubChem CID |
72202701
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| Appearance |
Light yellow to yellow solid powder
|
| LogP |
2.1
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| Hydrogen Bond Donor Count |
0
|
| Hydrogen Bond Acceptor Count |
8
|
| Rotatable Bond Count |
4
|
| Heavy Atom Count |
31
|
| Complexity |
681
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
CN1C=C2C=C(C(=CC2=N1)F)C(C3=NN=C4N3N=C(C=C4)C5=CN(N=C5)C6CC6)(F)F
|
| InChi Key |
QHXLXUIZUCJRKV-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C20H15F3N8/c1-29-9-11-6-14(15(21)7-17(11)27-29)20(22,23)19-26-25-18-5-4-16(28-31(18)19)12-8-24-30(10-12)13-2-3-13/h4-10,13H,2-3H2,1H3
|
| Chemical Name |
6-(1-cyclopropylpyrazol-4-yl)-3-[difluoro-(6-fluoro-2-methylindazol-5-yl)methyl]-[1,2,4]triazolo[4,3-b]pyridazine
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| Synonyms |
PLB 1001; Bozitinib; PLB-1001; PLB1001; APL-101; ...; 1440964-89-5; CBT101; CBT 101; CBT-101; Vebreltinib
|
| 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 |
| 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: 50~85 mg/mL (200.3~117.8 mM)
Ethanol: ~2.5 mg/mL (~5.9 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.90 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% 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 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 (4.90 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 (4.90 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 | 2.3564 mL | 11.7819 mL | 23.5638 mL | |
| 5 mM | 0.4713 mL | 2.3564 mL | 4.7128 mL | |
| 10 mM | 0.2356 mL | 1.1782 mL | 2.3564 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.
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