Savolitinib(AZD6094, HMPL-504)

Catalog No.S7674 Synonyms: Volitinib

Savolitinib(AZD6094, HMPL-504) Chemical Structure

Molecular Weight(MW): 345.36

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.

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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].

Assay
Methods Test Index PMID
Western blot
pMET / MET / pAKT / AKT / pERK / ERK; 

PubMed: 27472392     


Immunoblot analysis of H1993 and EBC-1 cells treated with 100 nM savolitinib for the indicated times.

27472392
Growth inhibition assay
Cell viability; 

PubMed: 27472392     


MET inhibitor GI50 determination in H1993 and EBC-1 cells treated as indicated for five days. Data shown are the mean ± S.D. normalized to vehicle control.

27472392
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

Cell Research:

[1]

+ Expand
  • 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.


    (Only for Reference)
Animal Research:

[1]

+ Expand
  • Animal Models: Female athymic mice
  • Formulation: 0.5% CMC-Na (oral); 0.25% DMSO, 10% Solutol, 10% Ethanol and 79.75% Saline (i.v.)
  • Dosages: 1.0, 2.5 and 10.0 mg/kg (oral); 2.5 mg/kg (i.v.)
  • Administration: oral administration/i.v.
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 16 mg/mL (46.32 mM)
Water Insoluble
Ethanol 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.

Chemical Information

Molecular Weight 345.36
Formula

C17H15N9

CAS No. 1313725-88-0
Storage powder
in solvent
Synonyms Volitinib

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Clinical Trial Information

NCT Number Recruitment interventions Conditions Sponsor/Collaborators Start Date Phases
NCT04121910 Not yet recruiting Drug: Savolitinib|Drug: Itraconazole Solid Tumour AstraZeneca|Parexel October 31 2019 Phase 1
NCT04118842 Not yet recruiting Drug: Savolitinib|Drug: Rifampicin Solid Tumors AstraZeneca October 7 2019 Phase 1
NCT03778229 Recruiting Drug: osimertinib|Drug: savolitinib Carcinoma AstraZeneca|Hutchison MediPharma January 9 2019 Phase 2
NCT03598244 Recruiting Drug: Savolitinib Primary Central Nervous System Neoplasm|Recurrent Diffuse Intrinsic Pontine Glioma|Recurrent Malignant Glioma|Recurrent Medulloblastoma|Refractory Diffuse Intrinsic Pontine Glioma|Refractory Malignant Glioma|Refractory Medulloblastoma National Cancer Institute (NCI) October 15 2018 Phase 1
NCT03258515 Completed Drug: AZD6094 200 mg|Other: Placebo|Drug: Moxifloxacin Solid Tumors AstraZeneca|Parexel September 6 2017 Phase 1

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c-Met Signaling Pathway Map

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID