含Src同源2结构域蛋白酪氨酸磷酸酶2抑制剂在肿瘤靶向和免疫治疗中的应用进展

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中文摘要：由PTPN11基因编码的含Src同源2结构域蛋白酪氨酸磷酸酶2(Src homology 2 domain-con-taining protein tyrosine phosphatase,SHP2)是细胞关键调节因子蛋白酪氨酸磷酸酶(protein tyrosine phospha-tase,PTP)家族的一员,在多种恶性肿瘤中高表达.一方面,SHP2通过介导RAS-MAPK,PI3K-AKT和JAK-STAT等信号通路调节肿瘤细胞的生理功能.另一方面,在肿瘤微环境中,SHP2与免疫抑制受体[如程序性死亡受体 1(programmed death-1,PD-1)、细胞毒性 T 淋巴细胞相关抗原 4(cytotoxic T lymphocyte-associated antigen-4,CTLA-4)等]结合,调节免疫细胞的功能,造成免疫微环境的抑制性.因此,SHP2在肿瘤中具有调节肿瘤细胞和免疫微环境的双重功能,提示其为极具价值的肿瘤治疗靶点.近年来,大量具有成药潜力的SHP2抑制剂进入临床试验,为肿瘤靶向治疗提供新的可能.目前SHP2抑制剂的研究已经取得一定成果,但仍存在较多耐药性、非特异性和毒性等问题.因此,需进一步研究SHP2抑制剂的成药性和靶向策略.本文对S HP2参与信号通路的调控机制和其在肿瘤和免疫微环境中的作用进行总结,并对S H P2抑制剂及其临床研究进展进行综述.

外文标题：Advances in Src homology 2 domain-containing protein tyrosine phosphatase inhibitors in tumor targeting and immunotherapy

外文摘要：Src homology 2 domain containing protein tyrosine phosphatase 2(SHP2),encoded by the PTPN11 gene,is a member of the PTP family of protein phosphatases.It plays a crucial role in regulating the physiological functions of tumor cells through the RAS-MAPK,PI3K-AKT,and JAK-STAT signaling pathways.Additionally,SHP2 binds to immunosuppressive receptors(such as PD-1 and CTLA4)in the tumor microenvironment,affecting immune cells'function and inhibiting the immune response.Due to its dual functions in regulating both tumor cells and the immune microenvironment,SHP2 is considered a valuable target for tumor therapy.In recent years,numerous SHP2 inhibitors with potential pharmaceutical applications have entered clinical trials,offering new prospects for targeted tumor therapy.However,challenges such as drug resistance,non-specificity,and toxicity still exist in the treatment of tumors using SHP2 inhibitors.Therefore,further researches on the druggability and targeting strategies of SHP2 inhibitors are necessary.This article provides a comprehensive summary of the regulatory mechanism of SHP2 in signaling pathways,the role in tumors and the immune microenvironment,and reviews the progress of clinical research on SHP2 inhibitors.

外文关键词：

Src homology 2 domain-containing protein tyrosine phosphatase 2tumorsignal pathwaytumor immune microenvironmentSrc homology 2 domain-containing protein tyrosine phosphatase inhibitor

作者：

石格格、王昭维、邱玥媛、何磊、李招招、史佳欣、赵博晨、韩笑、杜海琛、张英起

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作者单位：

西北大学生命科学学院,西安 710069

空军军医大学药学系生物制药学教研室,西安 710032

空军军医大学基础医学院,西安 710032

关键词：

含Src同源2结构域蛋白酪氨酸磷酸酶2 肿瘤信号通路肿瘤免疫微环境含Src同源2结构域蛋白酪氨酸磷酸酶2抑制剂

基金：

国家自然科学基金资助项目

项目编号：

82204259

出版年：

2024

中国新药杂志

中国医药科技出版社中国医药集团总公司中国药学会

中国新药杂志

CSTPCD北大核心

影响因子：1.039

ISSN：1003-3734

年,卷(期)：2024.33(15)