Preclinical antitumor activity of S-222611, an oral reversible tyrosine kinase inhibitor of epidermal growth factor receptor and human epidermal growth factor receptor 2.
Bottom Line: In evaluations with two patient-oriented models, the intrafemoral implantation model and the intracranial implantation model, S-222611 exhibited excellent activity and could be effective against bone and brain metastasis.Compared to neratinib and afatinib, irreversible EGFR/HER2 inhibitors, S-222611 showed equivalent or slightly weaker antitumor activity but a safer profile.These results indicated that S-222611 is a potent EGFR and HER2 inhibitor with substantially better antitumor activity than lapatinib at clinically relevant doses.
Affiliation: Discovery Research Laboratory for Innovative Frontier Medicines, Shionogi & Co., Ltd., Toyonaka, Osaka, Japan.Show MeSH
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Mentions: The in vivo antitumor activity of S-222611 was evaluated. Nude mice bearing NCI-N87 xenograft were treated orally with S-222611 or lapatinib. The changes of tumor volume over time are shown in Figure 1(a) (Fig. S1). S-222611 significantly inhibited the tumor growth in a dose-dependent manner. Comparison of ED50 between S-222611 and lapatinib (10.2 and 57.7 mg/kg, respectively, Table S2) indicated that the in vivo antitumor activity of S-222611 was approximately six times more potent than that of lapatinib. No body weight loss and no macroscopic toxicity were observed in the S-222611-treated mice.
Affiliation: Discovery Research Laboratory for Innovative Frontier Medicines, Shionogi & Co., Ltd., Toyonaka, Osaka, Japan.