Programmed cell death protein 1/programmed cell death 1 ligand 1(PD-1/PD-L1)protein-protein interaction represents an appealing target for cancer therapy.Several antibody drugs have been developed to target this inter...Programmed cell death protein 1/programmed cell death 1 ligand 1(PD-1/PD-L1)protein-protein interaction represents an appealing target for cancer therapy.Several antibody drugs have been developed to target this interaction,but they are less effective in the treatment of melanoma.To overcome the limitations,the first proteolysis-targeting chimeric(PROTAC)small molecules simultaneously targeting PD-L1and Src homology phosphotyrosyl phosphatase 2(SHP2)were designed.By employment of PD-1/PD-L1inhibitors BMS01 or BMS-37,SHP2 inhibitor SHP099 and E3 ligase ligands,a series of potent PD-L1 and SHP2 dual PROTACs were synthesized.The most promising compounds BS-7C-V2 and BS327V2 efficiently induced PD-L1 and SHP2 degradation and demonstrated significantly improved immune potency in B16-F10 and A375 cell lines.More importantly,the efficacy of BS-7C-V2 and BS327V2 in a B16-F10 transplanted mouse model was further evaluated based on their degradation ability in vivo.Taken together,our work qualifies the new dual PROTACs as a potent degrader of PD-L1 and SHP2.The biological and mechanism investigations with BS-7C-V2 and BS327V2 prove that dual PROTACs can play an anti-tumor role in vivo and in vitro,and can provide a new therapeutic strategy for melanoma.展开更多
SHP2 is the first identified oncogenic tyrosine phosphatase that promotes colorectal cancer(CRC)progression,and it is consistently overexpressed in CRC.It facilitates CRC oncogenesis by mediating downstream signaling ...SHP2 is the first identified oncogenic tyrosine phosphatase that promotes colorectal cancer(CRC)progression,and it is consistently overexpressed in CRC.It facilitates CRC oncogenesis by mediating downstream signaling cascades of receptor tyrosine kinases,including the RAS/ERK,JAK/STAT,and PI3K/AKT pathways,which are clinically associated with poor prognosis.Furthermore,SHP2 orchestrates immunosuppressive signaling networks by impairing cytotoxic T cell infiltration and changing the phenotype of tumor-associated macrophages within the tumor microenvironment(TME).Targeting SHP2 represents a dual therapeutic strategy in CRC:It concurrently regulates RTK signaling and reprograms the immunosuppressive TME.SHP2 inhibitors,administered both as monotherapy and in combination regimens,have advanced into clinical trial phases.Consequently,SHP2 serves as both a molecular target for precision oncology and an immunomodulatory node,positioning it as a high-priority candidate for CRC treatment.展开更多
目的研究人肝癌细胞中Pokemon对Shp2表达的影响。方法通过RT-PCR、Real time PCR和Western blot方法检测人肝癌细胞系QGY-7703和人正常肝细胞系HL-7702中Pokemon和Shp2的mRNA和蛋白表达水平差异;并通过瞬时转染si-Pokemon RNA沉默QGY-7...目的研究人肝癌细胞中Pokemon对Shp2表达的影响。方法通过RT-PCR、Real time PCR和Western blot方法检测人肝癌细胞系QGY-7703和人正常肝细胞系HL-7702中Pokemon和Shp2的mRNA和蛋白表达水平差异;并通过瞬时转染si-Pokemon RNA沉默QGY-7703细胞中Pokemon使其低表达,再检测Shp2的mRNA和蛋白水平变化。结果 Pokemon在人肝癌细胞系QGY-7703中的表达水平高于人正常肝细胞系HL-7702,Shp2的表达水平高低与Pokemon表达一致;在QGY-7703细胞中沉默Pokemon表达之后,Shp2的表达也相应降低。结论原癌基因Pokemon作为一种转录因子,可能调控Shp2的表达。展开更多
基金the National Natural Science Foundation of China(NSFC,No.82141216)Chunhui Program-Cooperative Research Project of the Ministry of Education+2 种基金Project of Frontier Technology Platform for Research Projects of Liaoning Provincial Department of Education in 2024Shenyang Young and Middle-aged Innovative Talents Support Program(No.RC210446)for financial supportsthe support from National-Local Joint Engineering Research Center for Molecular Biotechnology of Fujian&Taiwan TCM at Fujian University of Traditional Chinese Medicine。
文摘Programmed cell death protein 1/programmed cell death 1 ligand 1(PD-1/PD-L1)protein-protein interaction represents an appealing target for cancer therapy.Several antibody drugs have been developed to target this interaction,but they are less effective in the treatment of melanoma.To overcome the limitations,the first proteolysis-targeting chimeric(PROTAC)small molecules simultaneously targeting PD-L1and Src homology phosphotyrosyl phosphatase 2(SHP2)were designed.By employment of PD-1/PD-L1inhibitors BMS01 or BMS-37,SHP2 inhibitor SHP099 and E3 ligase ligands,a series of potent PD-L1 and SHP2 dual PROTACs were synthesized.The most promising compounds BS-7C-V2 and BS327V2 efficiently induced PD-L1 and SHP2 degradation and demonstrated significantly improved immune potency in B16-F10 and A375 cell lines.More importantly,the efficacy of BS-7C-V2 and BS327V2 in a B16-F10 transplanted mouse model was further evaluated based on their degradation ability in vivo.Taken together,our work qualifies the new dual PROTACs as a potent degrader of PD-L1 and SHP2.The biological and mechanism investigations with BS-7C-V2 and BS327V2 prove that dual PROTACs can play an anti-tumor role in vivo and in vitro,and can provide a new therapeutic strategy for melanoma.
基金Supported by Zhejiang Provincial Natural Science Foundation for Youths,No.QN25H160012Zhejiang Medical and Health Science and Technology Plan,No.2023RC006.
文摘SHP2 is the first identified oncogenic tyrosine phosphatase that promotes colorectal cancer(CRC)progression,and it is consistently overexpressed in CRC.It facilitates CRC oncogenesis by mediating downstream signaling cascades of receptor tyrosine kinases,including the RAS/ERK,JAK/STAT,and PI3K/AKT pathways,which are clinically associated with poor prognosis.Furthermore,SHP2 orchestrates immunosuppressive signaling networks by impairing cytotoxic T cell infiltration and changing the phenotype of tumor-associated macrophages within the tumor microenvironment(TME).Targeting SHP2 represents a dual therapeutic strategy in CRC:It concurrently regulates RTK signaling and reprograms the immunosuppressive TME.SHP2 inhibitors,administered both as monotherapy and in combination regimens,have advanced into clinical trial phases.Consequently,SHP2 serves as both a molecular target for precision oncology and an immunomodulatory node,positioning it as a high-priority candidate for CRC treatment.
文摘SHP2 (Src homology 2 domain-containing protein tyrosine phosphatase-2)是由Ptpn11基因编码的非受体型蛋白酪氨酸磷酸酶,通过RAS (rat sarcoma)-ERK (extracellular regulated protein kinases)信号通路的活化调控细胞生长、分化和凋亡,并参与PD-1 (programmed cell death protein 1)/PD-L1(programmed cell death ligand 1)通路的免疫监控,已成为有突破意义的抗癌药物新靶标.靶向SHP2变构位点的抑制剂通过稳定SHP2非活性构象而抑制磷酸酶催化功能,具有很好的成药性.但是,SHP2功能获得性突变(gainoffunction,简称GOF)导致一系列发育障碍疾病和肿瘤的发生,并对SHP2野生型变构抑制剂产生耐药性.本工作首次以靶向SHP2激活突变体的变构抑制剂为靶头,基于PROTACs(proteolysis-targeting chimeras)技术,设计合成了一系列全新SHP2小分子降解剂.其中先导化合物3f和4d保持了对突变型SHP2^(E76A)的酶抑制活性,而且对于野生型SHP2依赖的人食管鳞癌细胞KYSE-520和突变型SHP2^(N58S)人大细胞肺癌细胞NCI-H661都显示强效抗增殖活性,比相应变构抑制剂的活性提高了5~10倍,为治疗SHP2突变或活化导致的遗传性疾病或肿瘤提供了新的干预策略.
