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