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TAS-119, a novel selective Aurora A and TRK inhibitor, exhibits antitumor efficacy in preclinical models with deregulated activation of the Myc, β-Catenin, and TRK pathways

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Summary

Aurora kinase A, a mitotic kinase that is overexpressed in various cancers, is a promising cancer drug target. Here, we performed preclinical characterization of TAS-119, a novel, orally active, and highly selective inhibitor of Aurora A. TAS-119 showed strong inhibitory effect against Aurora A, with an IC50 value of 1.04 nmol/L. The compound was highly selective for Aurora A compared with 301 other protein kinases, including Aurora kinase B. TAS-119 induced the inhibition of Aurora A and accumulation of mitotic cells in vitro and in vivo. It suppressed the growth of various cancer cell lines harboring MYC family amplification and CTNNB1 mutation in vitro. In a xenograft model of human lung cancer cells harboring MYC amplification and CTNNB1 mutation, TAS-119 showed a strong antitumor activity at well-tolerated doses. TAS-119 induced N-Myc degradation and inhibited downstream transcriptional targets in MYCN-amplified neuroblastoma cell lines. It also demonstrated inhibitory effect against tropomyosin receptor kinase (TRK)A, TRKB, and TRKC, with an IC50 value of 1.46, 1.53, and 1.47 nmol/L, respectively. TAS-119 inhibited TRK-fusion protein activity and exhibited robust growth inhibition of tumor cells via a deregulated TRK pathway in vitro and in vivo. Our study indicates the potential of TAS-119 as an anticancer drug, especially for patients harboring MYC amplification, CTNNB1 mutation, and NTRK fusion.

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Data availability

Data generated or analyzed during this study are stored at Taiho Pharmaceutical Co., Ltd. and are not publicly available. Inquiries for data access may be sent to the corresponding author.

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Acknowledgments

We thank TAS-119 project members at Tsukuba Research Institute, Taiho Pharmaceutical Co., Ltd., for their support in this work. We thank Cactus Communications K.K. for proofreading the manuscript.

Funding

This study was funded by Taiho Pharmaceutical Co., Ltd.

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Authors and Affiliations

  1. Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd, 3 Okubo, Tsukuba, Ibaraki, 300-2611, Japan

    Akihiro Miura, Hiroshi Sootome, Naoya Fujita, Takamasa Suzuki, Hiroto Fukushima, Shinji Mizuarai, Norio Masuko, Kimihiro Ito, Akihiro Hashimoto, Tetsuya Sugimoto, Hidekazu Takahashi, Morihiro Mitsuya & Hiroshi Hirai

  2. Graduate School of Technology, Industrial and Social Sciences, Tokushima University, 770-8506, 2-1 Minamijosanjima-cho, Tokushima, Japan

    Akihiro Miura & Yoshihiro Uto

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  1. Akihiro Miura
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Contributions

Conception and design: Hiroshi Sootome, Hiroshi Hirai.

Development of methodology: Akihiro Miura, Hiroshi Sootome, and Norio Masuko.

Acquisition of data, animals, materials, and facilities: Akihiro Miura, Hiroshi Sootome, Norio Masuko, Kimihiro Ito, Takamasa Suzuki, and Akihiro Hashimoto.

Analysis and interpretation of data: Naoya Fujita, Hiroto Fukushima, and Shinji Mizuarai.

Writing, reviewing, and/or revising of the manuscript: Akihiro Miura, Hiroshi Hirai, and Yoshihiro Uto.

Administrative, technical, or material support: Akihiro Miura.

Study supervision: Hiroshi Hirai and Hiroshi Sootome.

Other (chemical design and synthesis): Tetsuya Sugimoto, Hidekazu Takahashi, and Morihiro Mitsuya.

Corresponding author

Correspondence to Hiroshi Hirai.

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Miura, A., Sootome, H., Fujita, N. et al. TAS-119, a novel selective Aurora A and TRK inhibitor, exhibits antitumor efficacy in preclinical models with deregulated activation of the Myc, β-Catenin, and TRK pathways. Invest New Drugs 39, 724–735 (2021). https://doi.org/10.1007/s10637-020-01019-9

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