Home Protein Tyrosine Kinase c-Met inhibitor Savolitinib (AZD6094)

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Savolitinib (AZD6094) c-Met inhibitor

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.
Savolitinib (AZD6094) c-Met inhibitor Chemical Structure

Chemical Structure

Molecular Weight: 345.36

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Quality Control

Cell Culture, Treatment & Working Concentration

Cell Lines Assay Type Concentration Incubation Time Formulation 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

Chemical Information, Storage & Stability

Molecular Weight 345.36 Formula

C17H15N9

 Storage (From the date of receipt)
CAS No. 1313725-88-0 Download SDF Storage of Stock Solutions

Synonyms HMPL-504, Volitinib Smiles CC(C1=CN2C=CN=C2C=C1)N3C4=NC(=CN=C4N=N3)C5=CN(N=C5)C

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

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Mass Concentration Volume Molecular Weight

In vivo
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Mechanism of Action

Targets/IC50/Ki
p-Met [1]
(Cell-free assay)
3 nM
c-Met [1]
(Cell-free assay)
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].
References

Applications

Methods Biomarkers Images PMID
Western blot pMET / MET / pAKT / AKT / pERK / ERK S7674-WB1 27472392
Growth inhibition assay Cell viability S7674-viability1 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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