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 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.