EAI045 - EGFR 抑制劑 - 生命科學(xué)試劑 - MedChemExpress

1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemEEAI045Cat. No.: HY-100213CAS No.: 1942114-09-1分式: CHFNOS分量: 383.4作靶點: EGFR作通路: JAK/STAT Signaling; Protein Tyrosine Kinase/RTK儲存式: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 months-20C 1 month溶解性數(shù)據(jù)體外實驗 DMSO : 28 mg/mL (73.03

2、 mM)* means soluble, but saturation unknown.Mass Solvent1 mg 5 mg 10 mg Concentration制備儲備液1 mM 2.6082 mL 13.0412 mL 26.0824 mL5 mM 0.5216 mL 2.6082 mL 5.2165 mL10 mM 0.2608 mL 1.3041 mL 2.6082 mL請根據(jù)產(chǎn)品在不同溶劑中的溶解度，選擇合適的溶劑配制儲備液，并請注意儲備液的保存式和期限。BIOLOGICAL ACTIVITY物活性 EAI045是突變體 EGFR 變構(gòu)抑制劑，在10 M ATP時抑制EGFR

3、，EGFRL858R，EGFRT790M 和EGFRL858R/T790M 的IC50 值分別為1.9，0.019，0.19 和 0.002 M。IC50 & Target EGFR EGFRL858R EGFRT790M EGFRL858R/T790M1.9 M (IC50) 0.019 M (IC50) 0.19 M (IC50) 0.002 M (IC50)1/2 Master of Small Molecules 您邊的抑制劑師www.MedChemE體外研究 EAI045 potently inhibits EGFR Y1173 phosphorylation in H1975 ce

4、lls (EC50=2 nM), but not in HaCaT cells.EAI045 is an inhibitor of the L858R/T790M mutant with 1000-fold selectivity versus wild type EGFR at 1 mMATP. Profiling of EAI045 against a panel of 250 protein kinases reveals exquisite selectivity; no other kinasesare inhibited by more than 20% at 1 M EAI045

5、 1. EAI045 has high potency and selectivity forL858R/T790M mutation. In L858R/T790M-mutant NSCLC cell line H1975 cells, EAI045 decreases but doesnot completely abolish the EGFR autophosphorylation. In stably transfected NIH-3T3 cells harboring theL858R/T790M EGFR mutant, EAI045 shows the same activi

6、ty. In L858R-mutant H3255 cells, EAI045exhibits moderate activity. In the HaCaT cells, a keratinocyte cell line with wild-type EGFR, EAI045 does notshow any activity of inhibiting EGFR phosphorylation. It confirms the selectivity of EAI045 for mutant EGFR2.體內(nèi)研究 In a genetically engineered mouse mode

7、l of L858R/T790Mmutant-driven lung cancer , remarkable tumorregression is observed in L858R/T790M-mutant mice treated with the combination of EAI045 and cetuximab.No response is seen in those mice treated with EAI045 alone. The same effect is seen in bothL858R/T790M/C797S- engineered Ba/F3 cells and

8、 in mice carrying the L858R/T790M/C797S tumorxenografts. These assays clearly show that EAI045 can overcome resistance from acquired T790M andC797S mutations 2.PROTOCOLCell Assay 1 For the experiment studying the effect of EGF pre-treatment on EAI045 target modulation, H1975 cells areharvested and p

9、lated in 0.5% FBS/RPMI Pen/Strep. On the following day, cells are pre-treated with 0.5%FBS/RPMI media with or without 10 ng EGF/mL for 5 minutes. Compound is added and assay is carried out1.MCE has not independently confirmed the accuracy of these methods. They are for reference only.Animal Mice: Ce

10、tuximab is administrated at 1 mg/mouse every other day by intraperitoneal injection. The TL, TD andAdministration 1 TLCS mice are monitored by MRI to quantify lung tumor burden before being assigned to various studytreatment cohorts, which are non-blinded and not formally randomized. All treated mic

11、e had an equal initialtumor burden. MRI evaluation is repeated every 2 weeks during treatment. The animals are imaged with arapid acquisition with relaxation enhancement sequence in the coronal and axial planes with a 1-mm slicethickness gating with respiratory rates. The tumor burden volumes are qu

12、antified 1.MCE has not independently confirmed the accuracy of these methods. They are for reference only.REFERENCES1. Jia Y, et al. Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors. Nature. 2016 Jun2;534(7605):129-32.2. Wang S, et al. EAI045: The fourth-generation EGFR inhibitor overcoming T790M and C797S resistance. Cancer Lett. 2017 Jan28;385:51-54.McePdfHeightCauti