TAS0728, A Covalent-binding, HER2-selective Kinase Inhibitor Shows Potent Antitumor Activity in Preclinical Models

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).