LY 2874455 Chemical Properties

Boiling point:

672.6±55.0 °C(Predicted)

Density 

1.44

storage temp. 

Store at -20°C

solubility 

≥44.4 mg/mL in DMSO; insoluble in H2O; ≥6.34 mg/mL in EtOH with gentle warming and ultrasonic

form 

solid

pka

12.93±0.40(Predicted)

color 

Pink to gray

CAS DataBase Reference

1254473-64-7

LY 2874455 Usage And Synthesis

Description

LY2874455 is a pan-FGFR inhibitor with IC50 of 2.8 nM, 2.6 nM, 6.4 nM, and 6 nM for FGFR1, FGFR2, FGFR3, and FGFR4, respectively, and also inhibits VEGFR2 activity with IC50 of 7 nM. Phase 1.

Uses

LY 2874455 is a pan-FGFR inhibitor which remain the focus of research for use in lung and bladder cancers.

Biological Activity

ly2874455 is a novel and potent fgfr inhibitor with ic50 value of 7 nm [1].fibroblast growth factor receptors (fgfrs) are receptors bind ligand of fgf family, which have a intracellular domain with tyrosine kinase activity. the binding of fgf triggers receptor dimerization and thus the activation of tyrosine kinase activity. activated tyrosine kinase phosphorylates various downstream factors to induce downstream signaling, including fgf substrate 2 (fgs2). this signaling pathway contributes to fgfr-mediated cell proliferation and migration, which are involved in tumor formation and progression.in huvecs cell line expressing fgfr1 and rt-112 cell line expressing fgfr3, ly2874455 treatment resulted in inhibition of fgf2 and fgf9 induced erk phosphorylation, which indicated the inhibitory activity of ly2874455 for fgfr1 and fgfr3 [1]. in snu-16 and kato-ш cell line, the inhibition of fgfr2 phosphorylation was also observed, which indicated a direct inhibition by ly2874455 [2]. additionally, when several multiple myeloma cancer cell lines were treated with lys2874455, the cell lines with chromosomal translocation that resulted in overexpression of fgfr3 were significantly more susceptible to the inhibition of ly2874455 [2]. it suggested fgfr was the specific target of ly2874455 inhibition.in rt-112, snu-16, opm-2 and nci-h460 xenograft tumor model, treatment of ly2874455 twice a day (1.5 mg/kg and 3 mg/kg) resulted in significant dose-dependent reduction of cellular level of phosphorylated fgfr, and also regression of tumor growth. it indicated the inhibitory activity of ly2874455 in vivo [2].

Synthesis

Methanol (57 mL) was added to a 250 mL three-necked round-bottomed flask equipped with a dosing funnel, nitrogen inlet, internal temperature probe and magnetic stirrer and cooled in an ice bath. Acetyl chloride (20 mL, 281.03 mmol) was added slowly and dropwise to the resulting solution through the addition funnel. Subsequently, 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-3-((E)-2-(1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-4-yl)vinyl)-1H-indazole (7.1 g, 11.59 mmol) solution in methanol (40 mL). After completion of addition, the ice bath was removed and the reaction mixture was warmed to room temperature and stirred for 4 hours. Upon completion of the reaction, the mixture was concentrated under vacuum to give a yellow foamy substance. The foam was dissolved in methanol (10 mL) and saturated aqueous sodium bicarbonate solution (120 mL) was slowly added. After stirring for 30 minutes at room temperature, the mixture was filtered, the solid was washed with water (100 mL) and dried under vacuum. Recrystallization by hot ethyl acetate/methanol/hexane mixed solvent afforded the title compound (R,E)-2-(4-(2-(2-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)vinyl)-1H-pyrazol-1-yl)ethanol as a white solid in 2.1 g yield (41% yield). Mass spectrum (electrospray ionization) m/z 444 [M + 1]+.

in vivo

target

FGFR1

IC 50

FGFR1: 2.8 nM (IC₅₀); FGFR2: 2.6 nM (IC₅₀); FGFR3: 6.4 nM (IC₅₀); FGFR4: 6 nM (IC₅₀)

References

[1] zhao, g s et al. , a novel, selective inhibitor of fibroblast growth factor receptors that shows a potent broad spectrum of antitumor activity in several tumor xenograft models. molecular cancer therapeutics. 2011, 10(11): 2200-2210.

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