Preclinical antitumor activity of S-222611, an oral reversible tyrosine kinase inhibitor of epidermal growth factor receptor and human epidermal growth factor receptor 2

Hidekazu Tanaka, Michinari Hirata, Satomi Shinonome, Toru Wada, Motofumi Iguchi, Keiji Dohi, Makiko Inoue, Yukichi Ishioka, Kanji Hojo, Tomomi Yamada, Tatsuya Sugimoto, Koichi Masuno, Ken ichi Nezasa, Norihito Sato, Kenji Matsuo, Shuji Yonezawa, Eugene P. Frenkel, Michitaka Shichijo

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

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. S-222611, a novel EGFR/HER2 kinase inhibitor, showed potent antitumor activity in the intracranial implantation model of breast cancer, due to its higher penetration into brain than lapatinib. This supports the potential clinical value of S-222611 for brain metastasis.

Original languageEnglish (US)
Pages (from-to)1040-1048
Number of pages9
JournalCancer Science
Volume105
Issue number8
DOIs
StatePublished - Aug 2014

Keywords

  • Antitumor activity
  • Epidermal growth factor receptor
  • Human epidermal growth factor receptor 2
  • Kinase inhibitor
  • S-222611

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Tanaka, H., Hirata, M., Shinonome, S., Wada, T., Iguchi, M., Dohi, K., Inoue, M., Ishioka, Y., Hojo, K., Yamada, T., Sugimoto, T., Masuno, K., Nezasa, K. I., Sato, N., Matsuo, K., Yonezawa, S., Frenkel, E. P., & Shichijo, M. (2014). Preclinical antitumor activity of S-222611, an oral reversible tyrosine kinase inhibitor of epidermal growth factor receptor and human epidermal growth factor receptor 2. Cancer Science, 105(8), 1040-1048. https://doi.org/10.1111/cas.12449