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.

中文翻译：

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抑制三阴性乳腺癌细胞生长的 CRM1 小分子抑制剂的发现和生物学评价

由染色体维持 1（CRM1，也称为 exportin-1）介导的核输出机制失调与各种人类疾病（如乳腺癌）密切相关。以前，我们将萝卜硫素及其合成类似物鉴定为 CRM1 的共价抑制剂。在此，我们描述了另一种萝卜硫素合成类似物 LFS-31 作为潜在 CRM1 抑制剂的发现和生物学评估。此外，我们通过分子模拟结合生物层干涉仪 (BLI) 研究了 LFS-31 与 CRM1 的可逆结合机制，发现 LFS-31 和 CRM1 组之间的结合亲和力相对较高 (KD = 43.1 ± 35.3 nM)。我们发现 LFS-31 对三阴性乳腺癌 (TNBC) 细胞的生长抑制比非 TNBC 细胞更强，并且对正常乳腺细胞的影响很小。用纳摩尔浓度的 LFS-31 对 TNBC 细胞进行药物治疗导致 IkBα 的核滞留，从而强烈抑制 NF-κB 转录活性并减弱细胞生长和增殖，这共同促成了抗肿瘤反应。据我们所知，这是第一项证明使用萝卜硫素类似物作为靶向 NF-κB 信号通路靶向治疗 TNBC 的有效 CRM1 抑制剂的研究。