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CO-1686

Cat. No. M2212
CO-1686 Structure
Synonym:

AVL-301, CNX-419

Size Price Availability Quantity
10mg USD 80 In stock
50mg USD 250 In stock
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Quality Control
Biological Activity

CO-1686 (also know as AVL-301) is an orally available small molecule, irreversible inhibitor of epidermal growth factor receptor (EGFR) with potential antineoplastic activity. CO-1686 selectively inhibits proliferation in the mutant-EGFR NSCLC cells with GI50 ranging from 7 to 32 nM, and induces apoptosis. In NSCLC cells with acquired resistance to CO-1686 in vitro, there was no evidence of additional mutations or amplification of the EGFR gene, but resistant cells exhibited signs of epithelial-mesenchymal transition and demonstrated increased sensitivity to AKT inhibitors. In vivo, CO-1686 caused dose-dependent and significant tumor growth inhibition in all EGFR-mutant models as well as human EGFRL858R- and EGFRL858R/T790M-expressing transgenic mice. CO-1686 is approximately 22-fold selective over WT EGFR (kinactt/Ki = (1.12 ± 0.14) x 104 M-1s-1).

Protocol
Cell Experiment
Cell lines HCC827 and HCC827-EPR cells
Preparation method Cell signaling analysis of HCC827 and HCC827-EPR HCC827 and HCC827-EPR cells were seeded at 1.5×106 cells per 10 cm2 dish in RPMI 1640, 10 % FBS, 2 mM L-glutamine, and 1% P/S and allowed to adhere overnight. Cells were treated with DMSO, 2 μM CO-1686, or 2 μM erlotinib for 72 hours and lysed. Lysis buffer contained 1X phenylmethanesulfonyl fluoride (Sigma; St. Louis, MO), 1X cell extraction buffer (Life Technologies), 1X protease inhibitor cocktail (Enzo Life Sciences; Farmingdale, NY), 1X phosphatase inhibitor cocktails I and II (EMD Chemicals; Gibbstown, NJ). Total protein concentration was determined using a standard Bradford and measured on a NanoDrop 2000 spectrophotometer (Thermo Scientific; Waltham, MA). Western blotting was performed on cell lysates normalized to 25 μg total protein in loading buffer (LI-COR; Lincoln, NE). Normalized lysates were run on SDS/PAGE and transferred to a nitrocellulose membrane (Life Technologies). The membrane was incubated in Qentix signal enhancement solution (Thermo Scientific), blocked, and incubated overnight at 4°C with primary antibodies (1:1000) from Cell Signaling (Danvers, MA). Membranes were washed, incubated with IRDye® secondary antibodies (LI-COR), washed again, and imaged on an Odyssey Fc (LI-COR).
Concentrations 2µM
Incubation time 72h
Animal Experiment
Animal models EGFR-L858R and EGFR-L858R-T790M;CCSP-rtTA transgenic mouse models
Formulation resuspended in warmed DMSO:Solutol HS15: PBS (5:15:80; v:v:v)
Dosages 50 mg/kg BID
Administration oral gavage
Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)
Species Mouse Rat Rabbit Guinea pig Hamster Dog
Weight (kg) 0.02 0.15 1.8 0.4 0.08 10
Body Surface Area (m2) 0.007 0.025 0.15 0.05 0.02 0.5
Km factor 3 6 12 8 5 20
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Chemical Information
Molecular Weight 555.55
Formula C27H28F3N7O3
CAS Number 1374640-70-6
Purity >99%
Solubility DMSO
Storage at -20°C
References

Discovery of a Mutant-Selective Covalent Inhibitor of EGFR that Overcomes T790M-Mediated Resistance in NSCLC.
Walter AO, et al. Cancer Discov. 2013 Dec;3(12):1404-15. PMID: 24065731.

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  Catalog
Abmole Inhibitor Catalog 2017




Keywords: CO-1686, AVL-301, CNX-419 supplier, EGFR/HER2, inhibitors

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