Funding information This study was sponsored by Shionogi & Co., Ltd.
Preclinical antitumor activity of S-222611, an oral reversible tyrosine kinase inhibitor of epidermal growth factor receptor and human epidermal growth factor receptor 2
Article first published online: 27 AUG 2014
© 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Volume 105, Issue 8, pages 1040–1048, August 2014
How to Cite
Cancer Sci 105 (2014) 1040–1048
- Issue published online: 27 AUG 2014
- Article first published online: 27 AUG 2014
- Accepted manuscript online: 18 MAY 2014 08:46PM EST
- Manuscript Accepted: 14 MAY 2014
- Manuscript Revised: 8 MAY 2014
- Manuscript Received: 16 FEB 2014
- Shionogi & Co., Ltd
- Antitumor activity;
- epidermal growth factor receptor;
- human epidermal growth factor receptor 2;
- kinase inhibitor;
Epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) are validated molecular targets in cancer therapy. Dual blockade has been explored and one such agent, lapatinib, is in clinical practice but with modest activity. Through chemical screening, we discovered a novel EGFR and HER2 inhibitor, S-222611, that selectively inhibited both kinases with IC50s below 10 nmol/L. S-222611 also inhibited intracellular kinase activity and the growth of EGFR-expressing and HER2-expressing cancer cells. In addition, S-222611 showed potent antitumor activity over lapatinib in a variety of xenograft models. 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. Considering the safer profile than for irreversible inhibitors, S-222611 could be an important option in future cancer therapy.