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Savolitinib (AZD6094) c-Met inhibitor

Name: Savolitinib (AZD6094)
Brand: Selleck Chemicals
SKU: S7674
Availability: InStock
Rating: 5 (19 reviews)

Cat.No.S7674

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.

Chemical Structure

Molecular Weight: 345.36

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Quality Control

Batch: Purity: 99.95%

99.95

Related Targets	EGFR VEGFR PDGFR FGFR Src MEK CSF-1R FLT3 HER2 c-Kit
Other c-Met Products	Tepotinib Dihexa SGX-523 Foretinib PHA-665752 SU11274 BMS-777607 JNJ-38877605 Tivantinib PF-04217903

Cell Culture, Treatment & Working Concentration

Cell Lines	Assay Type	Incubation Time	Activity Description	PMID
NCI-H441	Function assay	1 h	Inhibition of c-Met autophosphorylation in human NCI-H441 cells for 1 hr by ELISA, IC50=0.003 μM	25148209
NCI-H441	Proliferation assay	72 h	Antiproliferative activity against human NCI-H441 cells assessed as HGF-induced proliferation after 72 hrs by MTT assay, IC50=0.006 μM	25148209
Click to View More Cell Line Experimental Data

Solubility

In vitro
Batch:

DMSO : 69 mg/mL (199.79 mM)
(Moisture-contaminated DMSO may reduce solubility. Use fresh, anhydrous DMSO.)

Water : Insoluble

Ethanol : Insoluble

Molarity Calculator

Mass	Concentration	Volume	Molecular Weight
Mass value Mass unit	Concentration value Concentration unit	Volume value Volume unit	Molecular weight (g/mol)

Dilution Calculator Molecular Weight Calculator

In vivo batch selection In vivo Batch:
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Clear solution	5%DMSO 1 40%PEG300 2 5%Tween80 3 50%ddH2O Validated by Selleck labs. Should you need adjustments to this formulation, contact our sales team for custom testing.	5.000mg/ml (14.48mM)	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.
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.

In vivo Formulation Calculator (Clear solution)

Step 1: Enter information below (Recommended: An additional animal making an allowance for loss during the experiment)

Dosage: mg/kg

Average weight of animals: g

Dosing volume per animal: μL

Number of animals:

Step 2: Enter the in vivo formulation (This is only the calculator, not formulation. Please contact us first if there is no in vivo formulation at the solubility Section.)

% DMSO

% Tween 80

% ddH₂O

% DMSO

Calculation results:

Working concentration: mg/ml;

Method for preparing DMSO master liquid: mg drug pre-dissolved in μL DMSO ( Master liquid 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 master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH₂O, mix and clarify.

Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.

Note: 1. Please make sure the liquid is clear before adding the next solvent.
2. Be sure to add the solvent(s) in order. You must ensure that the solution obtained, in the previous addition, is a clear solution before proceeding to add the next solvent. Physical methods such
as vortex, ultrasound or hot water bath can be used to aid dissolving.

Chemical Information, Storage & Stability

Molecular Weight	345.36	Formula	C₁₇H₁₅N₉	Storage (From the date of receipt)	3 years-20°Cpowder
CAS No.	1313725-88-0	Download SDF		Storage of Stock Solutions	1 year-80°Cin solvent 1 month-20°Cin solvent
Synonyms	HMPL-504, Volitinib			Smiles	CC(C1=CN2C=CN=C2C=C1)N3C4=NC(=CN=C4N=N3)C5=CN(N=C5)C

Mechanism of Action

Targets/IC₅₀/Ki	p-Met (Cell-free assay) 3 nM c-Met (Cell-free assay) 5 nM
In vitro	Volitinib has exquisite kinase selectivity and excellent potency. 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). 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.
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. 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. 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.
References	[1] https://pubmed.ncbi.nlm.nih.gov/25148209/ [2] https://pubmed.ncbi.nlm.nih.gov/25248999/ [3] http://cancerres.aacrjournals.org/content/73/8_Supplement/3371

Applications

Methods	Biomarkers	Images	PMID
Western blot	pMET / MET / pAKT / AKT / pERK / ERK		27472392
Growth inhibition assay	Cell viability		27472392

Clinical Trial Information

(data from https://clinicaltrials.gov, updated on 2024-05-22)

NCT Number	Recruitment	Conditions	Sponsor/Collaborators	Start Date	Phases
NCT05888207	Completed	Healthy Male Subjects	AstraZeneca\|Parexel	June 2 2023	Phase 1
NCT05043090	Recruiting	Papillary Renal Cell Carcinoma	AstraZeneca	October 28 2021	Phase 3
NCT04606771	Active not recruiting	Non-Small Cell Lung Cancer	AstraZeneca	September 28 2020	Phase 2

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