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
More Info
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.]
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 |
mg/mL |
mM |
| Solubility |
| DMSO |
69.0 |
155.30 |
| Ethanol |
88.0 |
198.06 |
Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.
Preparing Stock Solutions
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.
Vangala D, Ladigan S, Liffers ST, Noseir S, Maghnouj A, Götze TM, Verdoodt B, Klein-Scory S, Godfrey L, Zowada MK, Huerta M, Edelstein DL, de Villarreal JM, Marqués M, Kumbrink J, Jung A, Schiergens T, Werner J, Heinemann V, Stintzing S, Lindoerfer D, Mansmann U, Pohl M, Teschendorf C, Bernhardt C, Wolters H, Stern J, Usta S, Viebahn R, Admard J, Casadei N, Fröhling S, Ball CR, Siveke JT, Glimm H, Tannapfel A, Schmiegel W, Hahn SA. Secondary resistance to anti-EGFR therapy by transcriptional reprogramming in patient-derived colorectal cancer models. Genome Med. 2021 Jul 16;13(1):116. doi: 10.1186/s13073-021-00926-7. PMID: 34271981.
