WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 205527
CAS#: 1254473-64-7
Description: LY2874455 is a novel and potent FGF/FGFR Inhibitor. It exhibits a potent activity against FGF/FGFR-mediated signaling in several cancer cell lines and shows an excellent broad spectrum of antitumor activity in several tumor xenograft models representing the major FGF/FGFR relevant tumor histologies including lung, gastric, and bladder cancers and multiple myeloma, and with a well-defined pharmacokinetic/pharmacodynamic relationship.
MedKoo Cat#: 205527
Name: LY2874455
CAS#: 1254473-64-7
Chemical Formula: C21H19Cl2N5O2
Exact Mass: 443.09158
Molecular Weight: 444.31
Elemental Analysis: C, 56.77; H, 4.31; Cl, 15.96; N, 15.76; O, 7.20
Synonym: LY2874455; LY 2874455; LY-2874455.
IUPAC/Chemical Name: (R,E)-2-(4-(2-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)vinyl)-1H-pyrazol-1-yl)ethanol.
InChi Key: GKJCVYLDJWTWQU-CXLRFSCWSA-N
InChi Code: InChI=1S/C21H19Cl2N5O2/c1-13(21-17(22)10-24-11-18(21)23)30-15-3-5-20-16(8-15)19(26-27-20)4-2-14-9-25-28(12-14)6-7-29/h2-5,8-13,29H,6-7H2,1H3,(H,26,27)/b4-2+/t13-/m1/s1
SMILES Code: C[C@H](C1=C(Cl)C=NC=C1Cl)OC2=CC3=C(NN=C3/C=C/C4=CN(CCO)N=C4)C=C2
Appearance: Yellow solid powder
Purity: >98% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: Soluble in DMSO, not in water
Shelf Life: >2 years if stored properly
Drug Formulation: This drug may be formulated in DMSO
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code: 2934.99.9001
| Biological target: | LY2874455 is a pan-FGFR inhibitor with IC50s of 2.8, 2.6, 6.4, 6 nM for FGFR1, FGFR2, FGFR3, FGFR4, respectively. |
| In vitro activity: | To confirm that LY (LY2874455) inhibits FGFR signaling, this study examined phosphorylation of the common FGFR receptor substrate, FRS2 (fibroblast growth factor receptor substrate 2), in KMCH and KMBC cells. As indicated in Fig. 1A, FRS2, was phosphorylated in both CCA cell lines at baseline; and incubation with LY blocked this phosphorylation, indicating inhibition of FGFR signaling cascades. Further studies demonstrated that LY also induces cell death in both the KMCH and KMBC cell lines (Fig. 1B). Reference: J Hepatol. 2018 Jun; 68(6): 1228–1238. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5960421/ |
| In vivo activity: | Already from day 4 of treatment this study observed significant inhibition of tumor growth compared to control-treated mice (Figure 5A). To confirm that LY2874455 reduced FGFR signaling in vivo, this study performed a kinetic study of FGFR signaling proteins. Tumors were harvested at 3, 24 and 48 h after last treatment (end of study) and protein lysates were subjected to Western blotting to analyze the phosphorylation levels of FRS2 and ERK. The endogenous level of phosphorylated FRS2 in the LS70x tumors was, as in the cell lines, below detection (data not shown). However, ERK phosphorylation was clearly reduced 3 h after treatment and remained reduced for at least 24 h (Figure 5B, quantified in Figure S4C). Reference: Cells. 2019 Feb; 8(2): 189. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6406403/ |
| Solvent | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| DMSO | 69.0 | 155.3 | |
| Ethanol | 88.0 | 198.06 |
The following data is based on the product molecular weight 444.31 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass | 1 mg | 5 mg | 10 mg |
|---|---|---|---|
| 1 mM | 1.15 mL | 5.76 mL | 11.51 mL |
| 5 mM | 0.23 mL | 1.15 mL | 2.3 mL |
| 10 mM | 0.12 mL | 0.58 mL | 1.15 mL |
| 50 mM | 0.02 mL | 0.12 mL | 0.23 mL |
| Formulation protocol: | 1. Kabashima A, Hirsova P, Bronk SF, Hernandez MC, Truty MJ, Rizvi S, Kaufmann SH, Gores GJ. Fibroblast growth factor receptor inhibition induces loss of matrix MCL1 and necrosis in cholangiocarcinoma. J Hepatol. 2018 Jun;68(6):1228-1238. doi: 10.1016/j.jhep.2018.01.026. Epub 2018 Mar 9. PMID: 29408314; PMCID: PMC5960421. 2. Wu D, Guo M, Philips MA, Qu L, Jiang L, Li J, Chen X, Chen Z, Chen L, Chen Y. Crystal Structure of the FGFR4/LY2874455 Complex Reveals Insights into the Pan-FGFR Selectivity of LY2874455. PLoS One. 2016 Sep 12;11(9):e0162491. doi: 10.1371/journal.pone.0162491. PMID: 27618313; PMCID: PMC5019380. 3. Hanes R, Munthe E, Grad I, Han J, Karlsen I, McCormack E, Meza-Zepeda LA, Stratford EW, Myklebost O. Preclinical Evaluation of the Pan-FGFR Inhibitor LY2874455 in FRS2-Amplified Liposarcoma. Cells. 2019 Feb 21;8(2):189. doi: 10.3390/cells8020189. PMID: 30795553; PMCID: PMC6406403. 4. Zhao G, Li WY, Chen D, Henry JR, Li HY, Chen Z, Zia-Ebrahimi M, Bloem L, Zhai Y, Huss K, Peng SB, McCann DJ. A novel, selective inhibitor of fibroblast growth factor receptors that shows a potent broad spectrum of antitumor activity in several tumor xenograft models. Mol Cancer Ther. 2011 Nov;10(11):2200-10. doi: 10.1158/1535-7163.MCT-11-0306. Epub 2011 Sep 7. PMID: 21900693. |
| In vitro protocol: | 1. Kabashima A, Hirsova P, Bronk SF, Hernandez MC, Truty MJ, Rizvi S, Kaufmann SH, Gores GJ. Fibroblast growth factor receptor inhibition induces loss of matrix MCL1 and necrosis in cholangiocarcinoma. J Hepatol. 2018 Jun;68(6):1228-1238. doi: 10.1016/j.jhep.2018.01.026. Epub 2018 Mar 9. PMID: 29408314; PMCID: PMC5960421. 2. Wu D, Guo M, Philips MA, Qu L, Jiang L, Li J, Chen X, Chen Z, Chen L, Chen Y. Crystal Structure of the FGFR4/LY2874455 Complex Reveals Insights into the Pan-FGFR Selectivity of LY2874455. PLoS One. 2016 Sep 12;11(9):e0162491. doi: 10.1371/journal.pone.0162491. PMID: 27618313; PMCID: PMC5019380. |
| In vivo protocol: | 1. Hanes R, Munthe E, Grad I, Han J, Karlsen I, McCormack E, Meza-Zepeda LA, Stratford EW, Myklebost O. Preclinical Evaluation of the Pan-FGFR Inhibitor LY2874455 in FRS2-Amplified Liposarcoma. Cells. 2019 Feb 21;8(2):189. doi: 10.3390/cells8020189. PMID: 30795553; PMCID: PMC6406403. 2. Zhao G, Li WY, Chen D, Henry JR, Li HY, Chen Z, Zia-Ebrahimi M, Bloem L, Zhai Y, Huss K, Peng SB, McCann DJ. A novel, selective inhibitor of fibroblast growth factor receptors that shows a potent broad spectrum of antitumor activity in several tumor xenograft models. Mol Cancer Ther. 2011 Nov;10(11):2200-10. doi: 10.1158/1535-7163.MCT-11-0306. Epub 2011 Sep 7. PMID: 21900693. |
1. Zhao G, Li WY, Chen D, Henry JR, Li HY, Chen Z, Zia-Ebrahimi M, Bloem L, Zhai Y, Huss K, Peng SB, McCann DJ. A novel, selective inhibitor of fibroblast growth factor receptors that shows a potent broad spectrum of antitumor activity in several tumor xenograft models. Mol Cancer Ther. 2011 Nov;10(11):2200-10. Epub 2011 Sep 7. PubMed PMID: 21900693.
LY2874455 is active against all 4 FGFRs, with a similar potency in biochemical assays. It exhibits a potent activity against FGF/FGFR-mediated signaling in several cancer cell lines and shows an excellent broad spectrum of antitumor activity in several tumor xenograft models representing the major FGF/FGFR relevant tumor histologies including lung, gastric, and bladder cancers and multiple myeloma, and with a well-defined pharmacokinetic/pharmacodynamic relationship. LY2874455 also exhibits a 6- to 9-fold in vitro and in vivo selectivity on inhibition of FGF- over VEGF-mediated target signaling in mice. Furthermore, LY2874455 did not show VEGF receptor 2-mediated toxicities such as hypertension at efficacious doses. Currently, this molecule is being evaluated for its potential use in the clinic.[source: Mol Cancer Ther; 10(11); 2200-10.]
