Sitravatinib Chemical Properties

Boiling point:

833.5±65.0 °C(Predicted)

Density 

1.417±0.06 g/cm3(Predicted)

storage temp. 

-20°C

solubility 

Soluble in DMSO (up to at least 25 mg/ml), or in Ethanol (up to at least 25 mg/ml)

form 

solid

pka

13.17±0.70(Predicted)

color 

Off-white

Stability:

Stable for 1 year from date of purchase as supplied. Solutions in DMSO or ethanol may be stored at -20°C for up to 1 month.

InChIKey

WLAVZAAODLTUSW-UHFFFAOYSA-N

SMILES

C1(C(NC2=CC=C(F)C=C2)=O)(C(NC2=CC=C(OC3C=CN=C4C=C(C5=NC=C(CNCCOC)C=C5)SC4=3)C(F)=C2)=O)CC1

Sitravatinib Usage And Synthesis

Description

Sitravatinib is a multi-kinase inhibitor. It inhibits 35 kinases (IC₅₀s = 0.5-5,550 nM) in a panel of 55 receptor tyrosine kinases (RTKs). Sitravatinib reduces proliferation of A-673, LPS141, MPNST, DDLS, and Saos-2 cancer cells (IC₅₀s = 1,750, 340.1, 705.7, 266, and 1,830 nM, respectively) and decreases phosphorylation of insulin-like growth factor 1 receptor (IGF1-R), PDGFRβ, and Akt in these same cells when used at concentrations ranging from 62.5 to 4,000 nM. It decreases tumor growth in LPS141 and MPNST mouse xenograft models when administered at a dose of 15 mg/kg per day.

Description

Sitravatinib, known as MGCD516, is a multikinase (MET, RET, AXL, NTRK1, or NTRK3 genes) inhibitor used in a phase 1/1b clinical trial (NCT02219711) for patients with advanced cancers (NCT02219711).

Uses

MGCD 516 is an intermediate used to prepare substituted thienopyridines as inhibitors of protein tyrosine kinase activity.

Synthesis

Step 2. Synthesis of N-(3-fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7- yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1 -dicarboxamide (147): Compound 146 (0.59 g, 0.81 mmol) was dissolved in dichloromethane (50 mL) in dichloromethane (50 mL) and trifluoroacetic acid (TFA, 3 mL) was added. The reaction mixture was stirred at room temperature for 18 hours. Upon completion of the reaction, the solution was concentrated to remove the solvent. The residue was partitioned between dichloromethane and 1 M sodium hydroxide solution and filtered to remove insoluble impurities. The organic phase was separated, washed sequentially with 1 M sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated to afford the target compound 147 (0.35 g, 69% yield).1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.40 (s, 1H), 10.01 (s, 1H), 8.55 (d, J = 1.6 Hz 1H), 8.51 (d, J = 5.3 Hz, 1H), 8.31 (s, 1H), 8.22 (d, J = 8.0 Hz, 1H), 7.92-7.87 (m, 2H), 7.65-7.61 (m, 2H), 7.52-7.43 (m, 2H), 7.17-7.12 (m, 2H), 6.64 (d, J = 5.5 Hz, 1H), 3.77 (s, 2H), 3.40 (t, J = 5.7 Hz, 2H), 3.23 (s, 3H), 2.64 (t, J = 5.7 Hz, 2H), 1.46 (br s, 4H). Mass spectrum (m/z): 630.1 (M + H).

in vivo

IC 50

Axl: 1.5 nM (IC₅₀); MER: 2 nM (IC₅₀); VEGFR3: 2 nM (IC₅₀); VEGFR2: 5 nM (IC₅₀); VEGFR1: 6 nM (IC₅₀); TrkA: 5 nM (IC₅₀); TrkB: 9 nM (IC₅₀); KIT: 6 nM (IC₅₀); FLT3: 8 nM (IC₅₀); DDR2: 0.5 nM (IC₅₀); DDR1: 29 nM (IC₅₀)

References

[1] PARAG P. PATWARDHAN. Significant blockade of multiple receptor tyrosine kinases by MGCD516 (Sitravatinib), a novel small molecule inhibitor, shows potent anti-tumor activity in preclinical models of sarcoma[J]. Oncotarget, 2015, 7 1: 4093-4109. DOI:10.18632/oncotarget.6547
[2] T. LEAL. MA 02.01 Evidence of Clinical Activity of Sitravatinib in Combination with Nivolumab in NSCLC Patients Progressing on Prior Checkpoint Inhibitors[J]. Journal of Thoracic Oncology, 2017. DOI:10.1016/j.jtho.2017.09.451
[3] WENTING DU. Sitravatinib potentiates immune checkpoint blockade in refractory cancer models.[J]. JCI insight, 2018. DOI:10.1172/jci.insight.124184

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