KPT-330 (Selinexor) is an orally active selective inhibitor of nuclear export (SINE) compound that inhibits the nuclear export protein XPO1 (also known as CRM1) [1]. KPT-330 covalently binds to the Cys528 site of XPO1, resulting in its irreversible inactivation [2]. KPT-330 can induce apoptosis, has inhibitory activity against various types of cancer cells, and can also enhance the effects of other chemotherapeutic drugs [3].
In vitro, KPT-330 (0-1000 nM) treatment of non-small cell lung cancer (NSCLC) cell lines for 72 h dose-dependently induced growth inhibition, promoted G1 phase arrest and apoptosis, and stimulated the activation of caspase-3 and caspase-9 [4]. KPT-330 (0-1000 nM) treatment of prostate cancer (PCa) cell lines for 72 h dose-dependently induced cell growth inhibition with IC50 values ranging from 43-700nM [5].
In vivo, oral treatment of mice with non-small cell lung cancer with KPT-330 (10 mg/kg) for 4 weeks significantly reduced tumor volume, reduced Ki-67-positive cells, and increased the percentage of TUNEL-positive cells, and this therapy had a synergistic effect with cisplatin [4]. Oral treatment of mice with pancreatic cancer with KPT-330 (20 mg/kg) for 3 weeks significantly reduced the expression of CRM1 protein in tumor samples, induced p27 nuclear staining, and enhanced the expression of the pro-apoptotic protein Bax [6].
References:
[1] Wang A Y, Liu H. The past, present, and future of CRM1/XPO1 inhibitors[J]. Stem cell investigation, 2019.
[2]Houghton P J, Kang M, Reynolds C P, et al. Pediatric Preclinical Testing Program (PPTP) stage 1 evaluation of the XPO1/CRM1 inhibitor KPT-330[J]. AACR (abstract LB-354), 2013.
[3]Liu S, Qiao W, Sun Q, et al. Chromosome region maintenance 1 (XPO1/CRM1) as an anticancer target and discovery of its inhibitor[J]. Journal of Medicinal Chemistry, 2021, 64(21): 15534-15548.
[4]Sun H, Hattori N, Chien W, et al. KPT-330 has antitumour activity against non-small cell lung cancer[J]. British journal of cancer, 2014, 111(2): 281-291.
[5]Gravina G L, Mancini A, Sanita P, et al. KPT-330, a potent and selective exportin-1 (XPO-1) inhibitor, shows antitumor effects modulating the expression of cyclin D1 and survivin in prostate cancer models[J]. BMC cancer, 2015, 15: 1-19.
[6]Kazim S, Malafa M P, Coppola D, et al. Selective nuclear export inhibitor KPT-330 enhances the antitumor activity of gemcitabine in human pancreatic cancer[J]. Molecular cancer therapeutics, 2015, 14(7): 1570-1581.
KPT-330（Selinexor）是一种具有口服活性的选择性核输出抑制剂（SINE）化合物，抑制核输出蛋白XPO1（又名CRM1）[1]。KPT-330与XPO1的Cys528位点共价结合，导致其不可逆失活[2]。KPT-330可诱导细胞凋亡，对各种类型的癌细胞具有抑制活性，还可以增强其他化疗药物的效果[3]。
在体外，KPT-330（0-1000 nM）处理非小细胞肺癌（NSCLC）细胞系72 h，剂量依赖性地诱导了生长抑制，促进G1期阻滞和细胞凋亡，刺激caspase-3和caspase-9的激活[4]。KPT-330（0-1000 nM）处理前列腺癌（PCa）细胞系72 h，剂量依赖性地诱导了细胞生长抑制，IC50值在43-700nM范围内[5]。
在体内，KPT-330（10 mg/kg）通过口服治疗患有非小细胞肺癌的小鼠4周，显著减小了肿瘤体积， 减少Ki-67阳性细胞，增加TUNEL阳性细胞百分比，且该疗法与顺铂具有协同作用[4]。KPT-330（20 mg/kg）通过口服治疗患有胰腺癌的小鼠3周，显著减少了肿瘤样本中CRM1蛋白的表达，诱导了p27核染色，增强了促凋亡蛋白Bax的表达[6]。