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Discovery and biological evaluation of a small‐molecule inhibitor of CRM1 that suppresses the growth of triple‐negative breast cancer cells
Author(s) -
Gao Jiujiao,
Chu Peng,
Liu Caigang,
Sun Zhaolin,
Liu Quentin,
Yang Yongliang
Publication year - 2021
Publication title -
traffic
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.677
H-Index - 130
eISSN - 1600-0854
pISSN - 1398-9219
DOI - 10.1111/tra.12802
Subject(s) - triple negative breast cancer , biology , cancer research , cell growth , cancer cell , nuclear export signal , cancer , microbiology and biotechnology , breast cancer , nucleus , cell nucleus , biochemistry , genetics
Dysregulation of the nuclear export machinery mediated by chromosomal maintenance 1 (CRM1, also known as exportin‐1), is closely associated with various human disorders, such as breast cancer. Previously, we identified sulforaphene and its synthetic analogues as covalent inhibitors of CRM1. Herein, we describe the discovery and biological evaluation of another sulforaphene synthetic analogue, LFS‐31, as a potential CRM1 inhibitor. In addition, we investigated the reversible binding mechanism of LFS‐31 with CRM1 through molecular simulations coupled with bio‐layer interferometry (BLI) and found relatively high binding affinity (KD = 43.1 ± 35.3 nM) between the LFS‐31 and CRM1 groups. We found that LFS‐31 exhibited a stronger growth suppression of triple‐negative breast cancer (TNBC) cells than non‐TNBC cells, and had minimal effect on normal breast cells. Pharmacological treatment of TNBC cells with LFS‐31 at nanomolar concentrations led to the nuclear retention of IkBα resulting in strong suppression of NF‐κB transcriptional activity and attenuated cell growth and proliferation, which collectively contributed to the antitumor responses. To the best of our knowledge, this is the first study to demonstrate the use of a sulforaphene analogue as a potent CRM1 inhibitor that targets the NF‐κB signaling pathway for the targeted therapy of TNBC.