Discovery of Highly Potent Daphnane Diterpenoids Uncovers Importin-β1 as a Druggable Vulnerability in Castration-Resistant Prostate Cancer.

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 . 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 significantly reduced the nuclear accumulation of key CRPC drivers, shutting down their downstream oncogenic signaling. Disruption of the predicted binding sites of on importin-β1 abolished this anti-CRPC effect. These findings suggest that importin-β1 is an effective therapeutic target in CRPC and that as the most potent importin-β1 inhibitor to date can be developed as therapeutics for treatment of this disease.