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Synthesis and in vitro characterization of ionone-based compounds as dual inhibitors of the androgen receptor and NF-κB

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Summary

Current therapeutic strategy for advanced prostate cancer is to suppress the androgen receptor (AR) signaling. However, lethal castration-resistant prostate cancer (CRPC) arises due to AR reactivation via multiple mechanisms, including mutations in the AR and cross-talk with other pathways such as NF-κB. We have previously identified two ionone-based antiandrogens (SC97 and SC245), which are full antagonists of the wild type and the clinically-relevant T877A, W741C and H874Y mutated ARs. Here, we discovered SC97 and SC245 also inhibit NF-κB. By synthesizing a series of derivatives of these two compounds, we have discovered a novel compound 3b that potently inhibits both AR and NF-κB signalling, including the AR F876L mutant. Compound 3b showed low micromolar antiproliferative activites in C4-2B and 22Rv1 cells, which express mutated ARs and are androgen-independent, as well as DU-145 and PC-3 cells, which exhibit constitutively activated NF-κB signalling. Our studies indicate 3b is effective against the CRPC cells.

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Abbreviations

AR:

Androgen receptor

Bic:

Bicalutamide

CRPC:

Castration-resistant prostate cancer

DHT:

Di-hydrotestosterone

WT:

Wild type

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Acknowledgments

This work was supported by The Cancer Research Society (J.W.). Postdoctoral fellowship from the CIHR/MCETC Strategic Training Program is grateful acknowledged (J.Z.).

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Segal Cancer Center, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, 3755 Cote-Ste-Catherine, Rd., Montreal, QC, H3T 1E2, Canada

    Weiguo Liu, Jinming Zhou, Guoyan Geng, Rongtuan Lin & Jian Hui Wu

  2. Departments of Oncology and Medicine, McGill University, 546 Pine Ave. W, Montreal, QC, H2W 1S6, Canada

    Rongtuan Lin & Jian Hui Wu

Authors
  1. Weiguo Liu
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  2. Jinming Zhou
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  3. Guoyan Geng
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  5. Jian Hui Wu
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Corresponding author

Correspondence to Jian Hui Wu.

Electronic supplementary material

Synthesis, 1H NMR and mass spectral analyses of 1b, 1d, 2a−2d and 4a−4f as well as cell lines and western blot analysis.

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Liu, W., Zhou, J., Geng, G. et al. Synthesis and in vitro characterization of ionone-based compounds as dual inhibitors of the androgen receptor and NF-κB. Invest New Drugs 32, 227–234 (2014). https://doi.org/10.1007/s10637-013-0040-y

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  • DOI: https://doi.org/10.1007/s10637-013-0040-y

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