1. Protein Tyrosine Kinase/RTK
  2. FGFR

LY2874455 

Cat. No.: HY-13304 Purity: 98.02%
Handling Instructions

LY2874455 is a pan-FGFR inhibitor with a similar potency for each enzyme. LY2874455 inhibits FGFR1, 2, 3, and 4 with IC50s of 2.8, 2.6, 6.4, and 6 nM, respectively.

For research use only. We do not sell to patients.
LY2874455 Chemical Structure

LY2874455 Chemical Structure

CAS No. : 1254473-64-7

Size Price Stock Quantity
Free Sample (0.5-1 mg)   Apply now  
10 mM * 1 mL in DMSO USD 172 In-stock
5 mg USD 156 In-stock
10 mg USD 252 In-stock
50 mg USD 816 In-stock
100 mg USD 1080 In-stock
200 mg   Get quote  
500 mg   Get quote  

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  • Biological Activity

  • Protocol

  • Technical Information

  • Purity & Documentation

  • References

Description

LY2874455 is a pan-FGFR inhibitor with a similar potency for each enzyme. LY2874455 inhibits FGFR1, 2, 3, and 4 with IC50s of 2.8, 2.6, 6.4, and 6 nM, respectively.

IC50 & Target

IC50: 2.8 nM (FGFR1), 2.6 nM (FGFR2), 6.4 nM(FGFR3), 6 nM (FGFR4)[1]

In Vitro

LY2874455 potently inhibits the Erk phosphorylation induced by FGF2 and FGF9 in both cell lines in a dose-dependent manner, with average IC50 values of 0.3 to 0.8 nM. LY2874455 indeed inhibits FGFR2 phosphorylation in SNU-16 and KATO-III cells, with estimated IC50 values of 0.8 and 1.5 nM, respectively. In addition, LY2874455 inhibits the phosphorylation of FRS2, an immediate downstream target of FGFR in these cell lines, again with a similar potency of 0.8 to 1.5 nM. Together, these results suggest that LY2874455 inhibits FGFR in the cell. The relative IC50 values of LY2874455 for KMS-11, OPM-2, L-363, and U266 cells are determined to be 0.57, 1.0, 60.4, and 290.7 nM, respectively[1].

In Vivo

LY2874455 exhibits a rapid, robust, dose-dependent inhibition of tumor growth in all 4 models tested. Importantly, this molecule causes a significant regression of tumor growth in the RT-112, SNU-16, and OPM-2 tumor models, especially when dosed at 3 mg/kg twice a day. Also, LY2874455 exhibits an excellent pharmacokinetic/pharmacodynamic relationship as shown by its dose-dependent inhibition of the tumor growth at TED50 and TED90 (1 and 3 mg/kg, respectively). When tested in the RT-112 tumor xenograft model on an intermittent dosing schedule (twice a day 1 week on and 1 week off or twice a day 2 days on and 2 days off), LY2874455 is also efficacious. When rats are dosed with LY2874455 at 1 and 3 mg/kg, which is 2.6- and 7.7-fold over the TED50 (0.39 mg/kg) obtained in the rat heart IVTI assay, respectively, there are no significant changes observed in blood pressure. However, when rats are dosed with LY2874455 at 10 mg/kg, which is 25.6-fold over the TED50, there are significant increases observed in arterial pressures[1].

Clinical Trial
References
Preparing Stock Solutions
Concentration Volume Mass 1 mg 5 mg 10 mg
1 mM 2.2507 mL 11.2534 mL 22.5068 mL
5 mM 0.4501 mL 2.2507 mL 4.5014 mL
10 mM 0.2251 mL 1.1253 mL 2.2507 mL
Please refer to the solubility information to select the appropriate solvent.
Kinase Assay
[1]

Reaction mixtures contained 8 mM Tris-HCl (pH 7.5), 10 mM HEPES, 5 mM dithiothreitol, 10 μM ATP, 0.5 μCi 33P-ATP, 10 mM MnCl2, 150 mM NaCl, 0.01% Triton X-100, 4% DMSO, 0.05 mg/mL poly(Glu:Tyr) (4:1, average molecular weight of 20-50 kDa), and 7.5, 7.5, and 16 ng of FGFR1, FGFR3, and FGFR4, respectively, and are incubated at room temperature for 30 minutes followed by termination with 10% H3PO4. The reaction mixtures are transferred to 96-well MAFB filter plates that are washed 3 times with 0.5% H3PO4. After air-drying, the plates are read with a Trilux reader[1]. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

Cell Assay
[1]

LY2874455 is dissolved in DMSO and stored, and then diluted with appropriate media before use[1].

The different multiple myeloma cancer cell lines KMS-11 and OPM-2 cells, L-363, and U266 cells are used. Cells (2,000 per well) are first grown in RPMI for 6 hours and treated with LY2874455 at 37°C for 3 days. The cells are stained at 37°C for 4 hours and then solubilized at 37°C for 1 hour. Finally, the plate is read at 570 nm using a plate reader[1]. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

Animal Administration
[1]

LY2874455 is formulated in 10% Acacia (Mice)[1].
LY2874455 is prepared in 1% hydroxyethylcellulose, 0.25% polysorbate 80, and 0.05% Dow Corning antifoam 1510-US in purified water (Rats)[1].

Mice[1]
RT-112, OPM-2 (DSMZ), SNU-16, and NCI-H460 cells (RT-112: 2×106 per animal; OPM-2: 107 per animal; SNU-16: 106 per animal; and NCI-H460: 3×106 per animal) are mixed with Matrigel (1:1) and implanted subcutaneously into the rear flank of the mice (female, CD-1 nu/nu for RT-112, OPM-2, and NCI-H460 cells and female, severe combined immunodeficient for SNU-16 cells). The implanted tumor cells grow as solid tumors. To test the efficacy of LY2874455 in these models, the animals are orally dosed with approximately 1 mg/kg (TED50) or 3 mg/kg (TED90) of LY2874455 in 10% Acacia once (every day) or twice a day after tumors reach approximately 150 mm3. The tumor volume and body weight are measured twice a week.
Rats[1]
Four male rats per group are dosed with vehicle (1% hydroxyethylcellulose, 0.25% polysorbate 80, and 0.05% Dow Corning antifoam 1510-US in purified water) on day 1 and LY2874455 (1, 3, and 10 mg/kg) on day 0. On day 1, at least 120 minutes of control data are collected following vehicle administration. On day 0, data are collected for approximately 20 hours beginning after the last animal is dosed. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

References
Molecular Weight

444.31

Formula

C₂₁H₁₉Cl₂N₅O₂

CAS No.

1254473-64-7

SMILES

ClC1=CN=CC(Cl)=C1[[email protected]@H](C)OC2=CC=C(NN=C3/C=C/C4=CN(CCO)N=C4)C3=C2

Storage
Powder -20°C 3 years
  4°C 2 years
In solvent -80°C 6 months
  -20°C 1 month
Shipping

Room temperature in continental US; may vary elsewhere

Solvent & Solubility

10 mM in DMSO

* "<1 mg/mL" means slightly soluble or insoluble. "≥" means soluble, but saturation unknown.

Purity: 98.02%

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Product Name:
LY2874455
Cat. No.:
HY-13304
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