摘要
转化生长因子-β(transforming growth factor-β, TGF-β)是一组生物学活性广泛的细胞因子,与受体结合后通过Smad与非Smad信号通路介导一系列的生物学反应,包括促细胞上皮-间质转化、促组织纤维化、促血管生成、促肿瘤的免疫逃逸、抑癌和促癌双重作用等。由于过度活化的TGF-β及其受体所介导的信号通路在多种疾病如恶性肿瘤及组织纤维化的发生、发展中具有重要的病理生理学作用,一些小分子抑制剂已被开发用于阻断该信号通路,从而为控制这些疾病提供一种新颖的治疗方案。其中, TGF-β配体抑制剂吡非尼酮已成功上市用于特发性肺纤维化治疗,治疗肿瘤、骨髓增生异常综合征的TGF-βI型受体激酶(ALK5)抑制剂LY2157299、EW-7197、LY3200882处于临床Ⅰ期至Ⅲ期试验阶段,多个其他TGF-β受体相关抑制剂如SB-431542、LY2109761、TP-0427736、IN-1130等处于临床前研究阶段。本文对以TGF-β及其受体为靶标的小分子抑制剂的最新研究进展进行了综述。
Transforming growth factor-β(TGF-β)belongs to a group of biologically active cytokines that bind to its receptors to activate Smad signaling and non-Smad signaling pathways.The biological functions of TGF-βinclude promoting cell epithelial-mesenchymal transition,tissue fibrosis,angiogenesis and tumor immune evasion,as well as dual effects of cancer suppression and cancer promotion.Given the fact that the ligand-and receptorsmediated abnormal activation of TGF-βsignaling pathways play an important role in the pathogenesis of multiple diseases such as malignant tumors and tissue fibrosis,more than a dozen small-molecule inhibitors have been developed to block the TGF-βsignaling pathways,providing a novel method for controlling the development of these diseases.At present,pirfenidone,an inhibitor for TGF-βproduction,has been approved for treatment of idiopathic pulmonary fibrosis,while the inhibitors of TGFβRI/ALK5 for therapeutics of tumors or myelodysplastic syndromes,including LY2157299,EW-7197 and LY3200882,are in the phase I to III clinical trials,with additional ones inhibiting TGFβRs such as SB-431542,LY2109761,TP-0427736,and IN-1130 being in the preclinical phase.This paper reviews recent advances in research of small-molecule inhibitors targeting TGF-βand its receptors.
作者
桑晓宏
王昊
游雪甫
杨信怡
SANG Xiao-hong;WANG Hao;YOU Xue-fu;YANG Xin-yi(Beijing Key Laboratory of Antimicrobial Agents,Institute of Medicinal Biotechnology,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100050,China;School of Pharmacy,Ningxia Medical University,Yinchuan 750004,China)
出处
《药学学报》
CAS
CSCD
北大核心
2019年第9期1538-1546,共9页
Acta Pharmaceutica Sinica
基金
国家自然科学基金资助项目(81273427)
北京协和医学院“协和青年基金”项目(33320140177/3332016139)
中国医学科学院医学与健康科技创新工程(2016-I2M-3-014)
“十三五”国家科技重大专项(2018ZX09721001)
