Synonym
EAI045; EAI-045; EAI 045.
IUPAC/Chemical Name
2-(5-fluoro-2-hydroxyphenyl)-2-(3-oxo-1H-isoindol-2-yl)-N-(1,3-thiazol-2-yl)acetamide
InChi Key
YTUFHOKUFOQRDF-UHFFFAOYSA-N
InChi Code
InChI=1S/C19H14FN3O3S/c20-12-5-6-15(24)14(9-12)16(17(25)22-19-21-7-8-27-19)23-10-11-3-1-2-4-13(11)18(23)26/h1-9,16,24H,10H2,(H,21,22,25)
SMILES Code
O=C(NC1=NC=CS1)C(C2=CC(F)=CC=C2O)N3CC4=C(C=CC=C4)C3=O
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
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:
EAI045 is an allosteric and the fourth-generation inhibitor of mutant EGFR with IC50s of 1.9, 0.019, 0.19 and 0.002 μM for EGFR, EGFRL858R, EGFRT790M and EGFRL858R/T790M at 10 μM ATP, respectively.
In vitro activity:
In L858R/T790M-mutant NSCLC cell line H1975 cells, EAI045 decreased but did not completely abolish the EGFR auto-phosphorylation. In stably transfected NIH-3T3 cells harboring the L858R/T790M EGFR mutant, EAI045 showed the same activity. In L858R-mutant H3255 cells, EAI045 exhibited moderate activity. In the HaCaT cells, a keratinocyte cell line with wild-type EGFR, EAI045 did not show any activity of inhibiting EGFR phosphorylation. These again confirmed the selectivity of EAI045 for mutant EGFR. Since dimerization of EGFR is required for its activation, these investigators hypothesized that the allosteric inhibitor was inactive for those asymmetric dimers/dimers between wild-type and mutant EGFR peptides. The investigators confirmed that EAI045 was markedly more active in dimerization-defective EGFR mutants. When combined with cetuximab, a monoclonal antibody that can block EGFR dimerization by preventing EGF ligand binding, EAI045 markedly inhibited the proliferation of Ba/F3 cells bearing L858R/T790M mutation. These in vitro studies proved that EAI045 is active and selective for T790M- harboring EGFR mutants that are in a monomer state.
Reference: Cancer Lett. 2017 Jan 28;385:51-54. https://linkinghub.elsevier.com/retrieve/pii/S0304-3835(16)30686-3
In vivo activity:
In a genetically engineered mouse model of L858R/T790M-mutant-driven lung cancer, the efficacy of EAI045 was tested alone and in combination with cetuximab. Remarkable tumor regression was observed in L858R/T790M-mutant mice treated with the combination of EAI045 and cetuximab. No response was seen in those mice treated with EAI045 alone. The same effect was seen in both L858R/T790M/C797S- engineered Ba/F3 cells and in mice carrying the L858R/T790M/C797S tumor xenografts. These assays clearly showed that EAI045 can overcome resistance from acquired T790M and C797S mutations.
Reference: Cancer Lett. 2017 Jan 28;385:51-54. https://linkinghub.elsevier.com/retrieve/pii/S0304-3835(16)30686-3
|
Solvent |
mg/mL |
mM |
| Solubility |
| DMSO |
76.0 |
198.23 |
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
383.40
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 |
In vitro protocol:
1. Wang S, Song Y, Liu D. EAI045: The fourth-generation EGFR inhibitor overcoming T790M and C797S resistance. Cancer Lett. 2017 Jan 28;385:51-54. doi: 10.1016/j.canlet.2016.11.008. Epub 2016 Nov 10. PMID: 27840244.
2. Wang S, Tsui ST, Liu C, Song Y, Liu D. EGFR C797S mutation mediates resistance to third-generation inhibitors in T790M-positive non-small cell lung cancer. J Hematol Oncol. 2016 Jul 22;9(1):59. doi: 10.1186/s13045-016-0290-1. PMID: 27448564; PMCID: PMC4957905.
In vivo protocol:
1. Wang S, Song Y, Liu D. EAI045: The fourth-generation EGFR inhibitor overcoming T790M and C797S resistance. Cancer Lett. 2017 Jan 28;385:51-54. doi: 10.1016/j.canlet.2016.11.008. Epub 2016 Nov 10. PMID: 27840244.
2. Jia Y, Yun CH, Park E, Ercan D, Manuia M, Juarez J, Xu C, Rhee K, Chen T, Zhang H, Palakurthi S, Jang J, Lelais G, DiDonato M, Bursulaya B, Michellys PY, Epple R, Marsilje TH, McNeill M, Lu W, Harris J, Bender S, Wong KK, Jänne PA, Eck MJ. Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors. Nature. 2016 Jun 2;534(7605):129-32. doi: 10.1038/nature17960. Epub 2016 May 25. PMID: 27251290; PMCID: PMC4929832.
1: Wang S, Tsui ST, Liu C, Song Y, Liu D. EGFR C797S mutation mediates resistance
to third-generation inhibitors in T790M-positive non-small cell lung cancer. J
Hematol Oncol. 2016 Jul 22;9(1):59. doi: 10.1186/s13045-016-0290-1. Review.
PubMed PMID: 27448564; PubMed Central PMCID: PMC4957905.
2: Jia Y, Yun CH, Park E, Ercan D, Manuia M, Juarez J, Xu C, Rhee K, Chen T,
Zhang H, Palakurthi S, Jang J, Lelais G, DiDonato M, Bursulaya B, Michellys PY,
Epple R, Marsilje TH, McNeill M, Lu W, Harris J, Bender S, Wong KK, Jänne PA, Eck
MJ. Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective
allosteric inhibitors. Nature. 2016 May 25;534(7605):129-32. doi:
10.1038/nature17960. PubMed PMID: 27251290; PubMed Central PMCID: PMC4929832.
