Savolitinib (AZD6094, HMPL-504)

c-Met (IC50 = 5 nM); p-Met (IC50 = 3 nM)

Volitinib exhibits exceptional potency and kinase selectivity [1]. In a panel of gastric cell lines, vitetinib exhibits a highly selective profile; it only potently inhibits cell growth in the lines that have dysregulated cMET (EC50 values 0.6 nM/L-12.5 nM/L)[2]. Volitinib shows minimal inhibition of P-gp (IC50 > 17 μM) and possesses high membrane permeability without causing efflux transport across the monolayer of Caco-2 cells. Volitinib does not significantly increase CYP1A2 and CYP3A4 in human hepatocytes or cause reversible or mechanism-based CYP inhibition in human liver microsomes[3].

The compound's half-time is 1.7 hours, and its clearance is 4.28 L/(h·kg) in a mouse pharmacokinetic study conducted on male ICR mice. The total plasma exposure is significantly higher despite its moderate oral bioavailability (F = 27.2%). In a U87MG subcutaneous xenograft model, volitinib exhibits dose-dependent inhibition of tumor growth[1]. Its treatment has minimal effect in a gastric cancer control model, but in 3/3 cMET-dysregulated gastric cancer patient-derived tumor xenograft models, it leads to pharmacodynamic modulation of c-MET signaling and strong tumor stasis[2]. The plasma protein binding rate of volitinib is moderate (60%–70% in rats, dogs, and humans; 40% in mice; 80% in monkeys). In rats, it is widely distributed to various organs, with high exposure in the liver and kidney and very low exposure in the brain, spinal cord, and testis in relation to the plasma level. Volitinib exhibits acceptable bioavailability at 27.2%, 42.6%, and 86.3%, respectively, and rapid oral absorption (Tmax<2.5 h) with high exposures in PK studies in mice, rats, and dogs. A low extraction ratio is evident from the in vivo clearance (CL), which is 11.0, 11.8, and 3.5 mL/min/kg in mice, rats, and dogs, respectively. For those species, the volume of distribution in steady state (Vss) is 0.4, 1.4, and 1.4 L/kg, respectively, suggesting a pattern of distribution that is moderate to low. In rats, vitexinib exhibits linear pharmacokinetics (PK) between 1 and 25 mg/kg, while in dogs, it is between 2 and 10 mg/kg. Dog food barely has an impact on its PK profile. However, in accordance with the in vitro metabolism result, volitinib in monkeys exhibits a noticeably high extraction ratio (CL=17.2 mL/min/kg). The low oral bioavailability (1.9%) of volitinib in monkeys is thought to be the consequence of excessive first-pass extraction, given the drug's rapid absorption (Tmax=1.9 h) and moderately low distribution (Vss=0.7 L/kg). Overall, volitinib's preclinical PK/ADME characteristics are favorable[3].

In 96-well plates, NCI-H441 cells are plated at a density of 15,000 cells/well in RPMI-1640 medium containing 10% FBS. Cells are incubated for a full night before being treated for one hour at 37 °C with progressively diluted test compounds. Following the removal of the medium, cells are lysed in a lysis buffer containing 100 μL per well and the following concentrations: 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, and 10 mg/mL Leupeptin. Overnight, the cell lysate-containing plates are stored at -80°C. The plates are gently mixed and thawed on ice the following day. To detect the p-c-Met signal, 25 μL/well of lysates are added to assay plates that have been pre-coated with anti-p-Met antibody. The measurements of p-c-Met are made at 450 and 570 nm.

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

[1]. J Med Chem . 2014 Sep 25;57(18):7577-89.

[2]. Mol Oncol . 2015 Jan;9(1):323-33.

[2]. Cancer Res (2013) 73 (8_Supplement): 3371.

C17H15N9

345.36

345.15

C, 59.12; H, 4.38; N, 36.50

1313725-88-0

Solid powder

C[C@@H](C1=CN2C=CN=C2C=C1)N3C4=NC(=CN=C4N=N3)C5=CN(N=C5)C

XYDNMOZJKOGZLS-NSHDSACASA-N

InChI=1S/C17H15N9/c1-11(12-3-4-15-18-5-6-25(15)10-12)26-17-16(22-23-26)19-8-14(21-17)13-7-20-24(2)9-13/h3-11H,1-2H3/t11-/m0/s1

3-[(1S)-1-imidazo[1,2-a]pyridin-6-ylethyl]-5-(1-methylpyrazol-4-yl)triazolo[4,5-b]pyrazine

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.08 mg/mL (6.02 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: 2.08 mg/mL (6.02 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (6.02 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)