Hexachlorophene, a selective SHP2 inhibitor, suppresses proliferation and metastasis of KRAS-mutant NSCLC cells by inhibiting RAS/MEK/ERK and PI3K/AKT signaling pathways
Hexachlorophene, a selective SHP2 inhibitor, suppresses proliferation and metastasis of KRAS-mutant NSCLC cells by inhibiting RAS/MEK/ERK and PI3K/AKT signaling pathways
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DOI：
10.1016/j.taap.2022.115988
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发表时间：
2022-03-22
影响因子：
3.8
通讯作者：
Wang, Fei
中科院分区：
文献类型：
--
作者：
Fu, Nai-jie;Xi, Rui-ying;Wang, Fei
Kirsten大鼠肉瘤病毒癌基因同源物（KRAS）突变占非小细胞肺癌（NSCLC）遗传变异的35%。由PTPN 11编码的含Src同源区2的蛋白酪氨酸磷酸酶2（SHP 2）通过影响细胞增殖、分化和免疫而密切参与RAS下游通路和许多肿瘤的发展。用小分子靶向SHP 2可能是治疗KRAS突变型（mut）NSCLC的有希望的途径。在此，通过对FDA批准的药物库的筛选，六氯酚（HCP）被鉴定为具有5.63 +/-0.75 μ M的IC 50值的SHP 2抑制剂。HCP特异性抑制SHP 2而不是其他磷酸酶。分子对接结果表明，HCP在SHP 2的催化结构域中显示出有利于亲核攻击的取向。HCP抑制多种KRAS-mut和KRAS-野生型细胞的活力，并诱导KRAS-mut细胞的衰老和凋亡。HCP可逆转KRAS-mut细胞的上皮-间质转化，抑制其转移，并通过抑制SHP 2磷酸化和SHP 2/Grb 2/Gab 1/SOS 1复合物的形成，抑制RAS/MEK/ERK和PI 3 K/AKT信号通路。综上所述，HCP可作为特异性SHP 2抑制剂，通过抑制RAF/MEK/ ERK和PI 3 K/AKT途径抑制KRAS-mut NSCLC细胞增殖和转移并诱导衰老。HCP作为开发用于治疗NSCLC的选择性SHP 2抑制剂的新化合物骨架值得进一步研究。
Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations account for 35% of the genetic alterations in non-small cell lung cancer (NSCLC). The Src-homology region 2-containing protein tyrosine phosphatase 2 (SHP2), encoded by PTPN11, is closely involved in RAS downstream pathways and development of many tumors by affecting cell proliferation, differentiation, and immunity. Targeting SHP2 with small molecules may be a promising avenue for the treatment of KRAS-mutant (mut) NSCLC. Herein, hexachlorophene (HCP) was identified as a SHP2 inhibitor with an IC50 value of 5.63 +/-& nbsp;0.75 mu M through screening of the FDA-approved drug library. HCP specifically inhibited SHP2 rather than other phosphatases. Molecular docking showed that HCP displayed an orientation favorable for nucleophilic attack in the catalytic domain of SHP2. HCP suppressed viability of multiple KRAS-mut and KRAS-wild type cells and induced senescence and apoptosis in KRAS-mut cells. Moreover, HCP reversed epithelial-mesenchymal transition to suppress metastasis in KRAS-mut cells, and inhibited the RAS/MEK/ERK and PI3K/AKT signaling pathways by suppression of SHP2 phosphorylation and formation SHP2/Grb2/Gab1/SOS1 complex. In summary, HCP can act as a specific SHP2 inhibitor to inhibit KRAS-mut NSCLC cell proliferation and metastasis and induce senescence through suppression of the RAF/MEK/ ERK and PI3K/AKT pathways. HCP warrants further investigation as a new compound skeleton for the development of selective SHP2 inhibitors for the treatment of NSCLC.