Savolitinib (AZD6094)

製品コードS7674 バッチS767401

印刷

化学情報

Chemical Structure Synonyms HMPL-504, Volitinib Storage
(From the date of receipt)		 3 years -20°C powder
1 years -80°C in solvent
化学式

C17H15N9
分子量 345.36 CAS No. 1313725-88-0
Solubility (25°C)* 体外 DMSO 16 mg/mL (46.32 mM)
Water Insoluble
Ethanol Insoluble
* <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.

溶剤液（一定の濃度）を調合する

生物活性

製品説明 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.
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].

プロトコル(参考用のみ)

細胞アッセイ 細胞株 NCI-H441 cells
濃度 --
反応時間 1 h
実験の流れ

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.
動物実験 動物モデル Female athymic mice
投薬量 1.0, 2.5 and 10.0 mg/kg (oral); 2.5 mg/kg (i.v.)
投与方法 oral administration/i.v.

Selleckの高級品が、幾つかの出版された研究調査結果（以下を含む）で使われた：

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
Synergistic Effects of Combination Therapy With AKT and mTOR Inhibitors on Bladder Cancer Cells [ Int J Mol Sci, 2020, 18;21(8):2825] PubMed: 32325639

長期の保管のために-20°Cの下で製品を保ってください。

人間や獣医の診断であるか治療的な使用のためにでない。

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