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MITF suppression by CH5552074 inhibits cell growth in melanoma cells

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Abstract

Purpose

Although treatment of melanoma with BRAF inhibitors and immune checkpoint inhibitors achieves a high response rate, a subset of melanoma patients with intrinsic and acquired resistance are insensitive to these therapeutics, so to improve melanoma therapy other target molecules need to be found. Here, we screened our chemical library to identify an anti-melanoma agent and examined its action mechanisms to show cell growth inhibition activity.

Methods

We screened a chemical library against multiple skin cancer cell lines and conducted ingenuity pathway analysis (IPA) to investigate the mechanisms of CH5552074 activity. Suppression of microphthalmia-associated transcription factor (MITF) expression levels was determined in melanoma cells treated with CH5552074. Cell growth inhibition activity of CH5552074 was evaluated in MITF-dependent melanoma cell lines.

Results

We identified an anti-melanoma compound, CH5552074, which showed remarkable cell growth inhibition activity in melanoma cell lines. The IPA results suggested that CH5552074-sensitive cell lines had activated MITF. In further in vitro studies in the melanoma cell lines, a knockdown of MITF with siRNA resulted in cell growth inhibition, which showed that CH5552074 inhibited cell growth by reducing the expression level of MITF protein.

Conclusions

These results suggest that CH5552074 can inhibit cell growth in melanoma cells by reducing the protein level of MITF. MITF inhibition by CH5552074 would be an attractive option for melanoma treatment.

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Acknowledgements

The authors thank Eigo Suyama, Nobuya Ishii, Yuko Aoki, Masahiro Aoki, and Osamu Kondoh for helpful discussions and Nobuhiro Oikawa for compound synthesis.

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Authors and Affiliations

  1. Research Division, Chugai Pharmaceutical Co., Ltd., 200 Kajiwara, Kamakura, Kanagawa, 247-8530, Japan

    Satoshi Aida, Yukiko Sonobe, Munehiro Yuhki, Kiyoaki Sakata, Toshihiko Fujii, Hiroshi Sakamoto & Takakazu Mizuno

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  1. Satoshi Aida
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  2. Yukiko Sonobe
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  3. Munehiro Yuhki
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  4. Kiyoaki Sakata
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  5. Toshihiko Fujii
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  6. Hiroshi Sakamoto
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  7. Takakazu Mizuno
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Correspondence to Satoshi Aida.

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All of the authors are employees of Chugai Pharmaceutical Co., Ltd.

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This article does not contain any studies with human participants or animals performed by any of the authors.

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Aida, S., Sonobe, Y., Yuhki, M. et al. MITF suppression by CH5552074 inhibits cell growth in melanoma cells. Cancer Chemother Pharmacol 79, 1187–1193 (2017). https://doi.org/10.1007/s00280-017-3317-6

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  • DOI: https://doi.org/10.1007/s00280-017-3317-6

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