Daphnane diterpenoids as potent and tolerable importin-b1 inhibitors to treat castration-resistant prostate cancer [RNA-Seq]

Importin-b1, a key member of karyopherins, is composed of 18-20 tandem repeats of the HEAT motif, each of which contains two antiparallel alpha helices linked by a turn. With the help of adaptor protein importin-α, importin-b1 recognizes cargo with NLS in the cytoplasm, and ferries the complex through the NPC into the nucleus. Several studies have shown that importin-b1 is overexpressed in some cancers, especially advanced prostate cancer, and is associated with poor prognosis and drug resistances.Here, the anti-CRPC (castration-resistant prostate cancer) screening of a natural diterpenoid library followed by target fishing led to the identification of a highly potent importin-b1 inhibitor, daphnane diterpenoid DD1.And the optimized analog is DD1-Br.To further dissect the influence of importin-b1 inhibitors on gene transcription programs, we analyzed RNA-seq transcriptomes of C4-2B cells with the treatment of DD1 (YDGY-3), DD1-Br (YDGY-3BR) or importazole (IPZ). C4-2B prostate cancer cells mRNA profiles of treatment with YDGY-3, YDGY-3BR or IPZ.