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SC912 inhibits AR-V7 activity in castration-resistant prostate cancer by targeting the androgen receptor N-terminal domain

Oncogene (2024)Cite this article

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Abstract

Androgen deprivation therapies (ADT) are the mainstay treatments for castration-resistant prostate cancer (CRPC). ADT suppresses the androgen receptor (AR) signaling by blocking androgen biosynthesis or inhibiting AR with antiandrogens that target AR’s ligand-binding domain (LBD). However, the ADT’s effect is short-lived, as the AR signaling inevitably arises again, which is frequently coupled with AR-V7 overexpression. AR-V7 is a truncated form of AR that lacks the LBD, thus being constitutively active in the absence of androgens and irresponsive to AR-LBD-targeting inhibitors. Though compelling evidence has tied AR-V7 to drug resistance in CRPC, pharmacological inhibition of AR-V7 is still an unmet need. Here, we discovered a small molecule, SC912, which binds to full-length AR as well as AR-V7 through AR N-terminal domain (AR-NTD). This pan-AR targeting relies on the amino acids 507–531 in the AR-NTD. SC912 also disrupted AR-V7 transcriptional activity, impaired AR-V7 nuclear localization and DNA binding. In the AR-V7 positive CRPC cells, SC912 suppressed proliferation, induced cell-cycle arrest, and apoptosis. In the AR-V7 expressing CRPC xenografts, SC912 attenuated tumor growth and antagonized intratumoral AR signaling. Together, these results suggested the therapeutic potential of SC912 for CRPC.

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Fig. 1: SC912 inhibited the transactivation of AR-V7 and AR-FL through direct binding.
Fig. 2: AR-NTD amino acids 507–531 are indispensable for the antagonistic activity of SC912.
Fig. 3: SC912 blocked AR-V7 driven AR signaling in CRPC cells.
Fig. 4: SC912 hampered the nuclear localization and chromatin binding for both AR-V7 and AR-FL.
Fig. 5: SC912 caused proliferation arrest and apoptosis in AR-V7 positive CRPC cells.
Fig. 6: SC912 repressed tumor growth and interrupted AR signaling in AR-V7 expressing CRPC xenografts.

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Data availability

The data used during this study are available from the corresponding author on request.

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Acknowledgements

This work was supported by operating grants from the Canadian Institutes of Health Research (to JHW). We are grateful to Drs Jun Luo (Johns Hopkins University), Stephen Plymate (University of Washington), Liangnian Song (Columbia University), S. Srivastava (Uniformed Services University), and O. Ogawa (Kyoto University) for generously providing plasmids as a gift for this work.

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  1. These authors contributed equally: Qianhui Yi, Xiaojun Han.

Authors and Affiliations

  1. Lady Davis Institute for Medical Research, SMBD-Jewish General Hospital, McGill University, 3755 Cote-Ste-Catherine, Rd, Montreal, QC, H3T 1E2, Canada

    Qianhui Yi, Xiaojun Han, Henry G. Yu, Huei-Yu Chen, Dinghong Qiu, Jie Su, Rongtuan Lin, Gerald Batist & Jian Hui Wu

  2. Departments of Oncology and Medicine, Faculty of Medicine, McGill University, Montreal, QC, Canada

    Qianhui Yi, Henry G. Yu, Huei-Yu Chen, Rongtuan Lin, Gerald Batist & Jian Hui Wu

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QY and JHW designed the research; QY, XH, HGY, HYC, DL, and JS performed the experiments; RL contributed plasmids; QY, GB, and JHW analyzed data; QY and JHW wrote the manuscript.

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Correspondence to Jian Hui Wu.

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Yi, Q., Han, X., Yu, H.G. et al. SC912 inhibits AR-V7 activity in castration-resistant prostate cancer by targeting the androgen receptor N-terminal domain. Oncogene (2024). https://doi.org/10.1038/s41388-024-02944-2

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