Savolitinib (AZD6094)

Catalog No.S7674 Batch:S767402

Technical Data

Formula

C₁₇H₁₅N₉

Molecular Weight

345.36

CAS No.

1313725-88-0

Solubility (25°C)*

In vitro

DMSO

69 mg/mL (199.79 mM)

Water

Insoluble

Ethanol

Insoluble

In vivo (Add solvents to the product individually and in order)

Clear solution

5%DMSO 1 40%PEG300 2 5%Tween80 3 50%ddH2O

5.0mg/ml

Taking the 1 mL working solution as an example, add 50 μL of 100 mg/ml clarified DMSO stock solution to 400 μL of PEG300, mix evenly to clarify it; add 50 μL of Tween80 to the above system, mix evenly to make it clear; then continue to add 500 μL of ddH2O to adjust the volume to 1 mL. The mixed solution should be used immediately for optimal results.

* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
* Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.)

Preparing Stock Solutions

Biological Activity

Description

Savolitinib (Volitinib, AZD6094, HMPL-504) is a novel, potent, and selective MET inhibitor currently in clinical development in various indications, including PRCC. The IC50 values of this compound for c-Met and p-Met are 5 nM and 3 nM, respectively. It shows exquisite selectivity for c-Met over 274 kinase.

Targets

p-Met ^[1] (Cell-free assay)	c-Met ^[1] (Cell-free assay)
3 nM	5 nM

In vitro

Volitinib has exquisite kinase selectivity and excellent potency^[1]. Volitinib displays a highly selective profile across a gastric cell line panel, potently inhibiting cell growth only in those lines with dysregulated cMET (EC50 values 0.6 nM/L-12.5 nM/L)^[2]. Volitinib has high membrane permeability without efflux transport across Caco-2 cell monolayer and exhibits negligible P-gp inhibition (IC50 > 17 μM). Volitinib shows no significant reversible or mechanism-based CYP inhibition in human liver microsomes, and no induction of CYP1A2 and CYP3A4 in human hepatocytes^[3].

In vivo

In a mouse pharmacokinetic study (male ICR mice), the clearance of the compound is 4.28 L/(h·kg) and the half-time is 1.7 h. Despite its moderate oral bioavailability (F = 27.2%), the overall plasma exposure is much higher. Volitinib demonstrates dose-dependent tumor growth inhibition in a U87MG subcutaneous xenograft model^[1]. Its treatment leads to pharmacodynamic modulation of c-MET signaling and potent tumor stasis in 3/3 cMET-dysregulated gastric cancer patient-derived tumor xenograft models, but has negligible activity in a gastric cancer control model^[2]. Volitinib has moderate plasma protein binding rate (60%∼70% in rat, dog, and human; 40% in mouse; 80% in monkey) and exhibits wide distribution to different organs in rat, with high exposures in liver and kidney, very low in brain, spinal cord and testis compared to the plasma level. In PK studies in mouse, rat and dog, Volitinib shows the rapid oral absorption (Tmax<2.5 h) with high exposures and the acceptable bioavailability at 27.2%, 42.6% and 86.3%, respectively. The in vivo clearance (CL) is 11.0, 11.8 and 3.5 mL/min/kg in mouse, rat and dog, respectively, revealing a low extraction ratio. The volume of distribution in steady state (Vss) is 0.4, 1.4 and 1.4 L/kg in those species, respectively, indicating a moderate to low distribution pattern. Volitinib also displays linear pharmacokinetics (PK) in the dose ranges of 1 to 25 mg/kg in rat and 2 to 10 mg/kg in dog. Food hardly affects its PK profile in dog. In contrast, volitinib in monkey shows a notably high extraction ratio (CL=17.2 mL/min/kg) consistent with the in vitro metabolism result. Considering the rapid absorption of volitinib (Tmax=1.9 h) and moderately low distribution (Vss=0.7 L/kg), the poor oral bioavailability (1.9%) of volitinib in monkey is considered to be the result of excessive first-pass extraction. Overall, volitinib exhibits favorable preclinical PK/ADME properties^[3].

Protocol (from reference)

Cell Assay:^{^[1]}	Cell lines NCI-H441 cells Concentrations -- Incubation Time 1 h Method NCI-H441 cells are plated at a density of 15,000 cells/well in RPMI-1640 medium with 10% FBS in 96-well plates. After incubation overnight, cells are then treated with serially diluted test compounds at 37 ℃ for 1 h. Then the medium is removed, and cells are lysed in 100 μL/well lysis buffer (1% NP-40, 20 mM Tris/pH 8.0, 137 mM NaCl, 10% glycerol, 2 mM EDTA, 1 mM activated sodium orthovanadate, 10 mg/mL Aprotinin, 10 mg/mL Leupeptin). The plates containing cell lysate are kept at -80℃ overnight. The next day, the plates are thawed on ice, mixed gently. 25 μL/well of lysates are added into the assay plates pre-coated with anti-p-Met antibody to detect p-c-Met signal. p-c-Met level is determined at 450 nm and 570 nm.
Animal Study:^{^[1]}	Animal Models Female athymic mice Dosages 1.0, 2.5 and 10.0 mg/kg (oral); 2.5 mg/kg (i.v.) Administration oral administration/i.v.

Cell Assay:^{^[1]}

Cell lines
NCI-H441 cells
Concentrations
--
Incubation Time
1 h
Method
NCI-H441 cells are plated at a density of 15,000 cells/well in RPMI-1640 medium with 10% FBS in 96-well plates. After incubation overnight, cells are then treated with serially diluted test compounds at 37 ℃ for 1 h. Then the medium is removed, and cells are lysed in 100 μL/well lysis buffer (1% NP-40, 20 mM Tris/pH 8.0, 137 mM NaCl, 10% glycerol, 2 mM EDTA, 1 mM activated sodium orthovanadate, 10 mg/mL Aprotinin, 10 mg/mL Leupeptin). The plates containing cell lysate are kept at -80℃ overnight. The next day, the plates are thawed on ice, mixed gently. 25 μL/well of lysates are added into the assay plates pre-coated with anti-p-Met antibody to detect p-c-Met signal. p-c-Met level is determined at 450 nm and 570 nm.

Animal Study:^{^[1]}

Animal Models
Female athymic mice
Dosages
1.0, 2.5 and 10.0 mg/kg (oral); 2.5 mg/kg (i.v.)
Administration
oral administration/i.v.

References

Selleck's Savolitinib (AZD6094) has been cited by 15 publications

Transgelin-2, a novel cancer stem cell-related biomarker, is a diagnostic and therapeutic target for biliary tract cancer [ BMC Cancer, 2024, 24(1):357]	PubMed: 38509504
Virtual screening and biological evaluation to identify pharmaceuticals potentially causing hypertension and hypokalemia by inhibiting steroid 11β-hydroxylase [ Toxicol Appl Pharmacol, 2023, 475:116638]	PubMed: 37499767
Patient-derived exosomes facilitate therapeutic targeting of oncogenic MET in advanced gastric cancer [ Sci Adv, 2023, 9(47):eadk1098]	PubMed: 38000030
Crizotinib attenuates cancer metastasis by inhibiting TGFβ signaling in non-small cell lung cancer cells [ Exp Mol Med, 2022, 54(8):1225-1235]	PubMed: 35999455
MET-induced CD73 restrains STING-mediated immunogenicity of EGFR-mutant lung cancer [ Cancer Res, 2022, CAN-22-0770]	PubMed: 36066413
The FAM3C locus that encodes interleukin-like EMT inducer (ILEI) is frequently co-amplified in MET-amplified cancers and contributes to invasiveness [ J Exp Clin Cancer Res, 2021, 40(1):69]	PubMed: 33596971
Targeted inhibition of c-MET by podophyllotoxin promotes caspase-dependent apoptosis and suppresses cell growth in gefitinib-resistant non-small cell lung cancer cells [ Phytomedicine, 2021, 80:153355]	PubMed: 33039730
Combination of type I and type II MET tyrosine kinase inhibitors as therapeutic approach to prevent resistance [ Mol Cancer Ther, 2021, molcanther.0344.2021]	PubMed: 34789563
CRISPR screens in cancer spheroids identify 3D growth-specific vulnerabilities [ Nature, 2020, 580(7801):136-141]	PubMed: 32238925
Molecular mechanisms of acquired resistance to MET tyrosine kinase inhibitors in patients with MET exon 14 mutant NSCLC. [ Clin Cancer Res, 2020, 10.1158/1078-0432.CCR-19-3608]	PubMed: 32034073

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