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A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
Discovery of a Small-Molecule Inhibitor Targeting the Androgen Receptor N-Terminal Domain for Castration-Resistant
Qianhui Yi1,2, Weiguo Liu1, Jung Hwa Seo1
1Lady Davis Institute for Medical Research, SMBD-Jewish General Hospital, McGill University, Montreal, Québec, Canada.
Abstract:
The current mainstay therapeutic strategy for advanced prostate cancer is to suppress androgen receptor (AR) signaling. However, castration-resistant prostate cancer (CRPC) invariably arises with restored AR signaling activity. To date, the AR ligand-binding domain (LBD) is the only targeted region for all clinically available AR signaling antagonists, such as enzalutamide (ENZ). Major resistance mechanisms have been uncovered to sustain the AR signaling in CRPC despite these treatments, including AR amplification, AR LBD mutants, and the emergence of AR splice variants (AR-Vs) such as AR-V7. AR-V7 is a constitutively active truncated form of AR that lacks the LBD; thus, it can not be inhibited by AR LBD-targeting drugs. Therefore, an approach to inhibit AR through the regions outside of LBD is urgently needed. In this study, we have discovered a novel small molecule SC428, which directly binds to the AR N-terminal domain (NTD) and exhibits pan-AR inhibitory effect. SC428 potently decreased the transactivation of AR-V7, ARv567es, as well as full-length AR (AR-FL) and its LBD mutants. SC428 substantially suppressed androgen-stimulated AR-FL nuclear translocation, chromatin binding, and AR-regulated gene transcription. Moreover, SC428 also significantly attenuated AR-V7-mediated AR signaling that does not rely on androgen, hampered AR-V7 nuclear localization, and disrupted AR-V7 homodimerization. SC428 inhibited in vitro proliferation and in vivo tumor growth of cells that expressed a high level of AR-V7 and were unresponsive to ENZ treatment. Together, these results indicated the potential therapeutic benefits of AR-NTD targeting for overcoming drug resistance in CRPC.
Insights
A new drug, SC428, targets the androgen receptor (AR) N-terminal domain (NTD) to inhibit prostate cancer growth. This novel approach overcomes resistance to current treatments like enzalutamide (ENZ) by targeting AR variants such as AR-V7.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Advanced prostate cancer treatment relies on suppressing androgen receptor (AR) signaling.
- Castration-resistant prostate cancer (CRPC) develops resistance through mechanisms like AR amplification, AR LBD mutants, and AR splice variants (AR-Vs), notably AR-V7.
- Existing AR antagonists targeting the ligand-binding domain (LBD) are ineffective against AR-V7 due to its lack of an LBD.
Purpose of the Study:
- To identify novel therapeutic strategies targeting AR signaling in CRPC, particularly for AR-V7-expressing tumors.
- To investigate a new small molecule, SC428, that targets the AR N-terminal domain (NTD) for pan-AR inhibitory effects.
Main Methods:
- Evaluated SC428's direct binding to the AR NTD.
- Assessed SC428's effect on the transactivation of full-length AR (AR-FL), AR LBD mutants, and AR variants (AR-V7, ARv567es).
- Measured SC428's impact on AR-FL nuclear translocation, chromatin binding, and gene transcription.
- Analyzed SC428's inhibition of AR-V7 signaling, nuclear localization, and homodimerization.
- Tested SC428's efficacy in inhibiting proliferation of resistant cancer cells in vitro and tumor growth in vivo.
Main Results:
- SC428 demonstrated potent inhibition of AR-V7, ARv567es, AR-FL, and AR LBD mutants.
- SC428 suppressed androgen-stimulated AR-FL activity and AR-V7-mediated signaling, independent of androgen.
- SC428 effectively inhibited AR-V7 nuclear localization and homodimerization.
- SC428 significantly reduced tumor growth in vivo and proliferation in vitro in enzalutamide-unresponsive, AR-V7-expressing cells.
Conclusions:
- SC428 is a novel small molecule that directly targets the AR NTD, exhibiting broad AR inhibitory activity.
- Targeting the AR NTD with SC428 offers a promising therapeutic strategy to overcome resistance mechanisms in CRPC, including those mediated by AR-V7.
- SC428 demonstrates significant potential for treating advanced prostate cancer refractory to current LBD-targeting therapies.
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