PRECLINICAL REPORTSAntitumor effects of novel highly hydrophilic and non-ATP-competitive MEK1/2 inhibitor, SMK-17Kiga, Masakia,c; Tanzawa, Fumiea; Iwasaki, Shihoa; Inaba, Fumia; Fujiwara, Kosakua; Iwadare, Hayatoa; Echigo, Tomokia; Nakamura, Yujib; Shibata, Tomoyukib; Suzuki, Kanaeb; Yasumatsu, Isaoa; Nakayama, Ayakoc; Sasazawa, Yukikoc; Tashiro, Etsuc; Imoto, Masayac; Kurakata, ShinichibAuthor Information aKasai R&D Center bShinagawa R&D Center, Daiichi Sankyo Co. Ltd, Tokyo cDepartment of Biosciences and Informatics, Faculty of Science and Technology, Keio University, Yokohama, Japan All supplementary digital content is available directly from the corresponding author. Correspondence to Masaki Kiga and Kosaku Fujiwara, Kasai R&D Center, Daiichi Sankyo, Co. Ltd, 1-16-13, Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan Tel: +81 336 800 151; fax: +81 356 964 264; e-mail: [email protected] and [email protected] Received May 20, 2011 Accepted August 27, 2011 Anti-Cancer Drugs: January 2012 - Volume 23 - Issue 1 - p 119-130 doi: 10.1097/CAD.0b013e32834c6a33 Buy Metrics Abstract The mitogen-activated protein kinase (MAPK) signal pathway plays a central role in regulating tumor cell proliferation, survival, and differentiation. The components of this pathway, Ras/Raf/MEK/ERK, are frequently activated in human cancers. Targeting this pathway is considered to be a promising anticancer strategy. In particular, MEK is an attractive drug target because of its high selectivity to ERK. We can expect potent growth inhibitory and proapoptotic effects by inhibiting MEK. Here, we report derivatives of N-[2-(2-chloro-4-iodo-phenylamino)-3,4-difluorophenyl]-methanesulfonamide as novel MEK1/2 inhibitors. Among these compounds, we found SMK-17 to be a potent MEK1/2 inhibitor with high aqueous solubility. The in-silico docking study suggested that SMK-17 is bound to an allosteric pocket of MEK1. The kinetic study and the kinase profiler analysis confirmed the allosteric nature of SMK-17. SMK-17 inhibited MEK1 kinase activity in a non-ATP-competitive manner and it was highly selective to MEK1 and 2. SMK-17 inhibited the growth of tumor cell lines in vitro. Especially, it seemed that cell lines harboring highly phosphorylated MEK1/2 and ERK1/2 were highly sensitive to SMK-17. Moreover, unlike previously reported MEK inhibitors, PD184352 or U0126, SMK-17 did not inhibit the phosphorylation of ERK5. In vivo, SMK-17 exhibited potent antitumor activity in animal models on oral administration. SMK-17 selectively blocked the MAPK pathway signaling without affecting other signal pathways, which resulted in significant antitumor efficacy without notable side effects. These findings suggest that SMK-17, an exquisitely selective, orally available MEK1/2 inhibitor, is a useful chemical biology tool for characterizing the function of MEK/MAPK signaling both in vitro and in vivo. © 2012 Lippincott Williams & Wilkins, Inc.