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Discovery of Highly Potent Daphnane Diterpenoids Uncovers Importin-β1 as a Druggable Vulnerability in
Jia-Luo Huang1, Xue-Long Yan1,2, Wei Li1
1School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510006, P.R. China.
Abstract:
Importins are overexpressed in many cancers and mediate the abnormal nuclear transport of oncogenic factors. The druggable potential of importins still remains unclear, largely because of the lack of potent inhibitors. Herein, the anti-castration-resistant prostate cancer (CRPC) screening of a Euphorbiaceae diterpenoid library followed by target fishing led to the identification of a highly potent importin-β1 inhibitor, daphnane diterpenoid DD1. DD1 selectively inhibited the growth and survival of CRPC cells at subnanomolar concentrations and completely blocked tumor growth in preclinical models at an extremely low dosage. Mechanistic studies revealed that targeting of importin-β1 by DD1 significantly reduced the nuclear accumulation of key CRPC drivers, shutting down their downstream oncogenic signaling. Disruption of the predicted binding sites of DD1 on importin-β1 abolished this anti-CRPC effect. These findings suggest that importin-β1 is an effective therapeutic target in CRPC and that DD1 as the most potent importin-β1 inhibitor to date can be developed as therapeutics for treatment of this disease.
Insights
A novel daphnane diterpenoid, DD1, potently inhibits importin-β1, a key driver in castration-resistant prostate cancer (CRPC). This discovery offers a promising new therapeutic strategy for CRPC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Importins facilitate nuclear transport of oncogenic factors, with overexpression linked to various cancers.
- The therapeutic potential of targeting importins remains largely unexplored due to a lack of potent inhibitors.
Purpose of the Study:
- To identify novel inhibitors of importin-β1 for the treatment of castration-resistant prostate cancer (CRPC).
- To evaluate the efficacy and mechanism of action of a newly identified importin-β1 inhibitor, DD1, in CRPC models.
Main Methods:
- Screening of a Euphorbiaceae diterpenoid library against CRPC cells.
- Target fishing to identify the molecular target of active compounds.
- In vitro and in vivo efficacy studies of DD1 in CRPC models.
- Mechanistic studies to elucidate the effect of DD1 on nuclear import and downstream signaling.
Main Results:
- Identification of daphnane diterpenoid DD1 as a highly potent importin-β1 inhibitor.
- DD1 demonstrated selective inhibition of CRPC cell growth and survival at subnanomolar concentrations.
- Complete tumor growth blockade in preclinical CRPC models at a very low dosage.
- DD1 significantly reduced nuclear accumulation of CRPC drivers by targeting importin-β1, thereby inhibiting oncogenic signaling.
Conclusions:
- Importin-β1 is a viable therapeutic target for castration-resistant prostate cancer.
- DD1 represents the most potent importin-β1 inhibitor identified to date and holds potential for CRPC therapeutic development.
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