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Published on: September 18, 2013
TAS0728, A Covalent-binding, HER2-selective Kinase Inhibitor Shows Potent Antitumor Activity in Preclinical Models
Hiroki Irie1, Kimihiro Ito2, Yayoi Fujioka2
1Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan. hiroki-irie@taiho.co.jp.
Abstract:
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).
Insights
A novel covalent inhibitor, TAS0728, selectively targets and inhibits activated Human Epidermal growth factor Receptor 2 (HER2) kinase activity. This compound demonstrates potent anti-cancer effects in preclinical models, offering a promising therapeutic option for HER2-activated cancers.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Activated Human Epidermal growth factor Receptor 2 (HER2) is a key target in various cancers.
- Existing HER2 inhibitors lack covalent binding and selectivity.
- There is a need for novel therapeutic strategies targeting HER2-driven malignancies.
Purpose of the Study:
- To report a novel covalent inhibitor, TAS0728, selective for HER2.
- To evaluate the biochemical and cellular activity of TAS0728.
- To assess the in vivo efficacy and safety of TAS0728 in preclinical cancer models.
Main Methods:
- Synthesis and characterization of TAS0728, a covalent HER2 inhibitor.
- Kinome-wide biochemical assays and cellular pharmacodynamics studies.
- In vivo efficacy studies in HER2-amplified breast cancer and HER2-driven cancer xenograft models.
Main Results:
- TAS0728 covalently binds HER2 at C805, selectively inhibiting its kinase activity.
- TAS0728 demonstrated high specificity for HER2 over wild-type EGFR and potently inhibited mutated and wild-type HER2 phosphorylation.
- TAS0728 induced apoptosis, tumor regression, and provided survival benefits in preclinical models with no evident toxicity.
Conclusions:
- TAS0728 is a novel, selective, covalent HER2 inhibitor with significant preclinical anti-cancer activity.
- TAS0728 represents a promising therapeutic candidate for HER2-activated cancers.
- Clinical trials are underway to further evaluate TAS0728 (NCT03410927).
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