Cell lines

NSCLC cells expressing mutant EGFR (HCC827, PC9, HCC827-EPR and NCI-H1975)

Preparation method

The solubility of this compound in DMSO is >27.8 mg/mL. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below - 20 ℃ for several months.

Reacting condition

72 hrs

Applications

In NSCLC cells expressing mutant EGFR (HCC827, PC9, HCC827-EPR and NCI-H1975), CO-1686 potently inhibited EGFR phosphorylation, with the IC50 values ranging from 62 to 187 nM. Moreover, CO-1686 selectively inhibited growth of NSCLC cells harboring mutant EGFR (GI50 = 7 ~ 32 nM) and induced apoptosis. In addition, CO-1686-resistant NSCLC cells showed signs of epithelial-mesenchymal transition and increased sensitivity to AKT inhibitors.

Animal models

Nude mice bearing lung NCI-H1975, LUM1868 and HCC827 cells, or squamous epidermoid A431 cells

Dosage form

3, 10, 30 and 100 mg/kg/day; p.o.; q.d. or b.i.d.

Applications

In all NSCLC EGFR mutant xenograft models, CO-1686 significantly inhibited tumor growth in a dose-dependent manner. In nude mice bearing NCI-H1975 or LUM1868 cells, CO-1686 caused tumor regressions. In the NCI-H1975 model, CO-1686 resulted in tumor regressions either given as 100 mg/kg once daily or as 50 mg/kg twice daily. Moreover, there was no significant change in body weight observed for these 2 dosing schedules.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

CO-1686 is an irreversible and orally delivered inhibitor of mutant EGFR with IC50 value of< 0.51 nM for recombinant EGFR L858R/T790M [1].

CO-1686 covalently modified Cys797 in the ATP binding pocket of the EGFR kinase. It also modified this residue in the EGFR L858R/T790M kinase domain. In the in vitro assay, CO-1686 potently inhibited EGFR L858R/T790M kinase with about 22-fold selectivity over wild-type EGFR. Among the 23 targets treated with CO-1686, EGFR del19, T790M, L858R/T790M and L858R mutants demonstrated the highest inhibition degree. In 4 NSCLC cell lines expressing mutant EGFR (HCC827, PC9, HCC827-EPR and NCI-H1975), CO-1686 potently inhibited cell proliferation with GI50 values of 7-32 nM. CO-1686 also inhibited some minor EGFR mutants including G719S, the exon 19 insertion and L861Q. In mice with NCI-H1975 xenografts, 100 mg/kg/day administration of CO-1686 caused tumor regressions [2].

References:
[1] Walter A O, Tjin R, Haringsma H, et al. CO-1686, an orally available, mutant-selective inhibitor of the epidermal growth factor receptor (EGFR), causes tumor shrinkage in Non-Small Cell Lung Cancer (NSCLC) with T790M resistance mutations. Mol Cancer Ther, 2011, 10(11 Suppl).
[2] Walter A O, Sjin R T T, Haringsma H J. Discovery of a mutant-selective covalent inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC.