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Ref Type Journal Article
PMID (30787176)
Authors Irie H, Ito K, Fujioka Y, Oguchi K, Fujioka A, Hashimoto A, Ohsawa H, Tanaka K, Funabashi K, Araki H, Kawai Y, Shimamura T, Wadhwa R, Ohkubo S, Matsuo K
Title TAS0728, A Covalent-binding, HER2-selective Kinase Inhibitor Shows Potent Antitumor Activity in Preclinical Models.
Journal Vol Issue Date Pages Journal Short Title
Molecular cancer therapeutics 18 4 2019 Apr 733-742 Mol Cancer Ther
URL
Abstract Text 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).

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
TAS0728 TAS0728 0 1
Drug Name Trade Name Synonyms Drug Classes Drug Description
TAS0728 TAS 0728|TAS-0728|TPC-107 HER2 Inhibitor 45 TAS0728 is a small molecule ERBB2 (HER2) inhibitor, which may have antitumor activity against HER2-amplified tumor models (PMID: 30787176, PMID: 32248641).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References