LY2801653 Chemical Properties

Boiling point:

795.3±60.0 °C(Predicted)

Density 

1.42±0.1 g/cm3(Predicted)

storage temp. 

Store at -20°C

solubility 

≥27.65 mg/mL in DMSO; insoluble in H2O; ≥5.02 mg/mL in EtOH with gentle warming and ultrasonic

form 

solid

pka

10.83±0.70(Predicted)

color 

White to yellow

InChI

InChI=1S/C30H22F2N6O3/c1-17-3-9-23(30(40)38(17)22-7-4-20(31)5-8-22)29(39)36-21-6-10-27(25(32)12-21)41-28-11-18-16-35-37(2)26(18)13-24(28)19-14-33-34-15-19/h3-16H,1-2H3,(H,33,34)(H,36,39)

InChIKey

QHADVLVFMKEIIP-UHFFFAOYSA-N

SMILES

C1(=O)N(C2=CC=C(F)C=C2)C(C)=CC=C1C(NC1=CC=C(OC2C(C3=CNN=C3)=CC3=C(C=2)C=NN3C)C(F)=C1)=O

LY2801653 Usage And Synthesis

Description

LY2801653 is an orally bioavailable MET kinase inhibitor (K_i = 2 nM). It also inhibits MST1R, Axl, MNK1/2, FLT3, DDR1, and DDR2 (IC₅₀s = 11, 2, 7, 7, 0.1, and 7 nM, respectively, in a cell-based assay). It inhibits MET autophosphorylation stimulated by hepatocyte growth factor (HGF) in H460 and S114 cells (IC₅₀s = 35.2 and 59.2 nM, respectively) and inhibits growth of Ba/F3 cells transfected with MET-activating mutations (IC₅₀s = 12-248 nM). LY2801653 (0.01-10 μM) completely blocks cell scattering induced by HGF in DU145 cells. It reduces tumor growth in MET autocrine (U-87MG) and MET over-expression (H441) mouse xenograft models when administered at doses of 4 and 12 mg/kg.

Description

MET is a tyrosine kinase that leads to downstream activation of several pathways including RAS and MAPK.?As a result, it is quite possible that MET inhibition can be active in RAS mutant tumors and maybe associated with EGFR resistance in NSCLC.?Two MET inhibitors, tivantinib and onartuzumab, have been examined in KRAS mutant NSCLC with others in clinical trials at this time.

Uses

LY2801653(Merestinib), a c-MET inhibitor developed by Lilly, has shown promising therapeutic effects in many solid tumors by targeting c-MET/HGFR and is used in clinical trials to treat a variety of oncolytic indications.

Mechanism of action

LY2801653(Merestinib) inhibited phosphorylation of eIF4E in MV4-11, MM6 and AML-PT cells, blocked the cell cycle in the G0/G1 phase by decreasing the expression of cyclin A2 and cyclin B1, arrested colony formation, induced apoptosis in MV4-11 cells and exhibited antileukemic properties in vivo.

Clinical Use

Preclinical testing also has shown merestinib to inhibit several other receptor tyrosine oncokinases including MST1R, FLT3, AXL, MERTK, TEK, ROS1, and NTRK1/2/3.

target

c-MET

References

[1] yan s b et al. , ly2801653 is an orally bioavailable multi-kinase inhibitor with potent activity against met, mst1r, and other oncoproteins, and displays anti-tumor activities in mouse xenograft models. invest new drugs. 2012, 31: 833-844.

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