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. Rociletinib (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, Rociletinib (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. Rociletinib (CO-1686) is approximately 22-fold selective over WT EGFR (kinactt/Ki = (1.12 ± 0.14) x 104 M-1s-1).
| 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 |
| Molecular Weight | 555.55 |
| Formula | C27H28F3N7O3 |
| CAS Number | 1374640-70-6 |
| Solubility (25°C) | DMSO 50 mg/mL |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| 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 Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 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 Compound A of 10 mg/kg.
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