PT - JOURNAL ARTICLE AU - Irie, Hiroki AU - Ito, Kimihiro AU - Fujioka, Yayoi AU - Oguchi, Kei AU - Fujioka, Akio AU - Hashimoto, Akihiro AU - Ohsawa, Hirokazu AU - Tanaka, Kenji AU - Funabashi, Kaoru AU - Araki, Hikari AU - Kawai, Yuichi AU - Shimamura, Tadashi AU - Wadhwa, Renu AU - Ohkubo, Shuichi AU - Matsuo, Kenichi TI - TAS0728, A Covalent-binding, HER2-selective Kinase Inhibitor Shows Potent Antitumor Activity in Preclinical Models AID - 10.1158/1535-7163.MCT-18-1085 DP - 2019 Apr 01 TA - Molecular Cancer Therapeutics PG - 733--742 VI - 18 IP - 4 4099 - http://mct.aacrjournals.org/content/18/4/733.short 4100 - http://mct.aacrjournals.org/content/18/4/733.full SO - Mol Cancer Ther2019 Apr 01; 18 AB - Activated HER2 is a promising therapeutic target for various cancers. Although several reports have described HER2 inhibitors in development, no covalent-binding inhibitor selective for HER2 has been reported. Here, we report a novel compound TAS0728 that covalently binds to HER2 at C805 and selectively inhibits its kinase activity. Once TAS0728 bound to HER2 kinase, the inhibitory activity was not affected by a high ATP concentration. A kinome-wide biochemical panel and cellular assays established that TAS0728 possesses high specificity for HER2 over wild-type EGFR. Cellular pharmacodynamics assays using MCF10A cells engineered to express various mutated HER2 genes revealed that TAS0728 potently inhibited the phosphorylation of mutated HER2 and wild-type HER2. Furthermore, TAS0728 exhibited robust and sustained inhibition of the phosphorylation of HER2, HER3, and downstream effectors, thereby inducing apoptosis of HER2-amplified breast cancer cells and in tumor tissues of a xenograft model. TAS0728 induced tumor regression in mouse xenograft models bearing HER2 signal–dependent tumors and exhibited a survival benefit without any evident toxicity in a peritoneal dissemination mouse model bearing HER2-driven cancer cells. Taken together, our results demonstrated that TAS0728 may offer a promising therapeutic option with improved efficacy as compared with current HER2 inhibitors for HER2-activated cancers. Assessment of TAS0728 in ongoing clinical trials is awaited (NCT03410927).This article is featured in Highlights of This Issue, p. 731