PDF(Pubmed)
Abstract：
The overactivation of NF-κB signaling is a key hallmark for the pathogenesis of extranodal natural killer/T cell lymphoma (ENKTL), a very aggressive subtype of non-Hodgkin\'s lymphoma yet with rather limited control strategies. Previously, we found that the dysregulated exportin-1 (also known as CRM1) is mainly responsible for tumor cells to evade apoptosis and promote tumor-associated pathways such as NF-κB signaling.
Herein we reported the discovery and biological evaluation of a potent small molecule CRM1 inhibitor, LFS-1107. We validated that CRM1 is a major cellular target of LFS-1107 by biolayer interferometry assay (BLI) and the knockdown of CRM1 conferred tumor cells with resistance to LFS-1107.
We found that LFS-1107 can strongly suppresses the growth of ENKTL cells at low-range nanomolar concentration yet with minimal effects on human platelets and healthy peripheral blood mononuclear cells. Treatment of ENKTL cells with LFS-1107 resulted in the nuclear retention of IkBα and consequent strong suppression of NF-κB transcriptional activities, NF-κB target genes downregulation and attenuated tumor cell growth and proliferation. Furthermore, LFS-1107 exhibited potent activities when administered to immunodeficient mice engrafted with human ENKTL cells.
Therefore, LFS-1107 holds great promise for the treatment of ENKTL and may warrant translation for use in clinical trials.
Yang\'s laboratory was supported by the National Natural Science Foundation of China (Grant: 81874301), the Fundamental Research Funds for Central University (Grant: DUT22YG122) and the Key Research project of \'be Recruited and be in Command\' in Liaoning Province (Personal Target Discovery for Metabolic Diseases).
Herein we reported the discovery and biological evaluation of a potent small molecule CRM1 inhibitor, LFS-1107. We validated that CRM1 is a major cellular target of LFS-1107 by biolayer interferometry assay (BLI) and the knockdown of CRM1 conferred tumor cells with resistance to LFS-1107.
We found that LFS-1107 can strongly suppresses the growth of ENKTL cells at low-range nanomolar concentration yet with minimal effects on human platelets and healthy peripheral blood mononuclear cells. Treatment of ENKTL cells with LFS-1107 resulted in the nuclear retention of IkBα and consequent strong suppression of NF-κB transcriptional activities, NF-κB target genes downregulation and attenuated tumor cell growth and proliferation. Furthermore, LFS-1107 exhibited potent activities when administered to immunodeficient mice engrafted with human ENKTL cells.
Therefore, LFS-1107 holds great promise for the treatment of ENKTL and may warrant translation for use in clinical trials.
Yang\'s laboratory was supported by the National Natural Science Foundation of China (Grant: 81874301), the Fundamental Research Funds for Central University (Grant: DUT22YG122) and the Key Research project of \'be Recruited and be in Command\' in Liaoning Province (Personal Target Discovery for Metabolic Diseases).
摘要：
背景：NF-κB信号的过度激活是结外自然杀伤/T细胞淋巴瘤（ENKTL）发病机理的关键标志，非霍奇金淋巴瘤的一个非常积极的亚型，但有相当有限的控制策略。以前,我们发现，失调的输出蛋白-1（也称为CRM1）主要负责肿瘤细胞逃避凋亡和促进肿瘤相关通路，如NF-κB信号传导。
方法：本文报道了一种有效的小分子CRM1抑制剂的发现和生物学评价，LFS-1107.我们通过生物层干涉测定法（BLI）验证了CRM1是LFS-1107的主要细胞靶标，并且CRM1的敲低使肿瘤细胞对LFS-1107具有抗性。
结果：我们发现LFS-1107可以在低范围纳摩尔浓度下强烈抑制ENKTL细胞的生长，但对人血小板和健康外周血单核细胞的影响最小。用LFS-1107处理ENKTL细胞导致IkBa的核保留，并因此强烈抑制NF-kB转录活性，NF-kB靶基因下调并减弱肿瘤细胞的生长和增殖。此外，LFS-1107在施用于移植了人ENKTL细胞的免疫缺陷小鼠时表现出有效的活性。
结论：因此，LFS-1107对ENKTL的治疗具有很大的希望，并且可能需要在临床试验中使用翻译。
资助：杨的实验室得到了国家自然科学基金（资助：81874301）的资助，中央大学基础研究基金（授予：DUT22YG122）和辽宁省“招募和指挥”重点研究项目（代谢性疾病的个人目标发现）。
方法：本文报道了一种有效的小分子CRM1抑制剂的发现和生物学评价，LFS-1107.我们通过生物层干涉测定法（BLI）验证了CRM1是LFS-1107的主要细胞靶标，并且CRM1的敲低使肿瘤细胞对LFS-1107具有抗性。
结果：我们发现LFS-1107可以在低范围纳摩尔浓度下强烈抑制ENKTL细胞的生长，但对人血小板和健康外周血单核细胞的影响最小。用LFS-1107处理ENKTL细胞导致IkBa的核保留，并因此强烈抑制NF-kB转录活性，NF-kB靶基因下调并减弱肿瘤细胞的生长和增殖。此外，LFS-1107在施用于移植了人ENKTL细胞的免疫缺陷小鼠时表现出有效的活性。
结论：因此，LFS-1107对ENKTL的治疗具有很大的希望，并且可能需要在临床试验中使用翻译。
资助：杨的实验室得到了国家自然科学基金（资助：81874301）的资助，中央大学基础研究基金（授予：DUT22YG122）和辽宁省“招募和指挥”重点研究项目（代谢性疾病的个人目标发现）。
