新型靶向细胞凋亡的小分子抑制剂的研究进展与临床应用潜力  

Research Progress and Clinical Application Potential of Novel Small Molecule Inhibitors Targeting Apoptosis

作　　者：石珊 邱妙珍[1] 杨大俊[1,2] SHI Shan;QIU Miaozhen;YANG Dajun(State Key Laboratory of Oncology in South China,Guangdong Provincial Clinical Research Center for Cancer,Sun Yat-sen University Cancer Center,Guangzhou 510060,China;Ascentage Pharma(Suzhou)Co.Ltd,Suzhou 215100,China)

机构地区：[1]华南恶性肿瘤防治全国重点实验室,广东省恶性肿瘤临床医学研究中心,中山大学肿瘤防治中心,广州510060 [2]苏州亚盛药业有限公司,苏州215100

出　　处：《中国细胞生物学学报》2025年第3期661-678,共18页Chinese Journal of Cell Biology

摘　　要：凋亡是程序性细胞死亡的一种形式,是多细胞生物用来清除受损或冗余细胞的自然过程。这一过程受到高度精细的调控,其失衡往往与癌症、自身免疫性疾病、神经炎症发生等密切相关。细胞对凋亡的抵抗性成为了一个显著特征,这往往源自于内源性及外源性生存信号与促凋亡信号之间错综复杂的失衡状态。促凋亡和抗凋亡信号通过调控Bcl-2蛋白家族的促凋亡成员,决定了细胞的生存或死亡。多年来,研究者们一直致力于开发并研究各类药物或途径以促进肿瘤细胞凋亡,进而达到控制肿瘤发展的目的。其中以Bcl-2家族蛋白、IAPs家族成员及MDM2-p53通路为靶点的小分子抑制剂在促进肿瘤细胞凋亡的研究中表现出显著的临床应用潜力。该综述旨在系统性阐述这些关键靶点的基本结构与生理功能,早期抑制剂的疗效及其局限性,并详细探讨由亚盛医药研究团队开发的新型靶向细胞凋亡的小分子抑制剂在抗肿瘤治疗中的研究进展与应用前景。Apoptosis represents a form of programmed cell death,integral to the physiological processes by which multicellular organisms eliminate damaged or surplus cells.This highly regulated phenomenon is frequently disrupted,correlating strongly with various pathological conditions,including malignancies,autoimmune disorders,and neuroinflammatory diseases.A hallmark of cancer is the resistance to apoptosis,which often stems from a complex dysregulation between intrinsic and extrinsic survival signals and pro-apoptotic factors.The balance between pro-apoptotic and anti-apoptotic signals,primarily mediated by members of the Bcl-2 protein family,ultimately dictates cellular fate.Over the years,considerable effort has been devoted to the identification and development of pharmacological agents aimed at inducing apoptosis in neoplastic cells to inhibit tumor progression.Particularly,small molecule inhibitors targeting the Bcl-2 family,IAPs(inhibitors of apoptosis proteins),and the MDM2-p53 signaling pathway have demonstrated substantial clinical potential in facilitating tumor cell apoptosis.This review seeks to systematically elucidate the fundamental structures and physiological roles of these critical targets,assess the efficacy and limitations of early-stage inhibitors,and provide a comprehensive overview of the advancements and future applications of novel small molecule inhibitors developed by Ascentage Pharma research team,specifically designed to enhance apoptotic pathways in oncological therapy.

关 键 词：细胞凋亡 小分子抑制剂 BCL-2 IAPS MDM2-P53 

分 类 号：R73[医药卫生—肿瘤]