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中国生物工程杂志

CHINA BIOTECHNOLOGY
中国生物工程杂志
中国生物工程杂志  2024, Vol. 44 Issue (2/3): 94-111    DOI: 10.13523/j.cb.2305045
综述     
肿瘤靶向抑制剂的PROTACs设计及在抗肿瘤新药开发中的应用*
李婧绮,吴定宇,谭睿**()
西南交通大学生命科学与工程学院 成都 610031
PROTACs’ Design of Tumor-targeting Inhibitors and Their Use in the Development of New Anti-tumor Drugs
LI Jingqi,WU Dingyu,TAN Rui**()
College of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China
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摘要：

蛋白质的非正常表达往往会直接或间接导致癌症的发生。目前,靶向特定蛋白质的小分子抑制剂在肿瘤治疗领域中得到了广泛使用。然而,小分子抑制剂存在易使机体产生耐药性、靶蛋白范围有限及毒性较高等问题,限制了其临床应用。由此,蛋白质水解靶向嵌合体技术应运而生。蛋白质水解靶向嵌合体(proteolysis-targeting chimaeras, PROTACs)是一种人工合成的小分子化合物,由靶蛋白配体、连接体和E3泛素连接酶配体三部分组成。它可以利用人体自身的泛素-蛋白酶体系统(ubiquitin-proteasome system, UPS)使目标蛋白质泛素化并降解,在一定程度上解决了过度使用小分子抑制剂而产生耐药性的问题,且具有低毒性的优点。因此,综合我国发病率排名前五的癌症,总结在癌症领域利用已有小分子抑制剂开发的PROTACs的设计及应用,以期予以新药研究人员启发,扩展小分子靶向抑制剂的使用,突破难以成药位点的药物选择。
关键词： 蛋白质水解靶向嵌合体;  蛋白质降解;  癌症;  泛素-蛋白酶体系统    
Abstract:

Abnormal protein expression often leads directly or indirectly to the development of cancer. Currently, small-molecule inhibitors that target specific proteins are widely used in tumor therapy. However, small-molecule inhibitors have problems such as susceptibility to drug resistance, limited range of target proteins, and high toxicity, which limit their clinical application. As a result, proteolysis-targeting chimaera technology has emerged. Proteolysis targeting chimaeras (PROTACs) are a type of synthetic small-molecule compound consisting of target protein ligand, linker and E3 ubiquitin ligase ligand. It can use the human body’s own ubiquitin-proteasome system (UPS) to ubiquitinate and degrade the target protein, which to some extent solves the problem of drug resistance caused by overuse of small-molecule inhibitors, and has the advantage of low toxicity. Therefore, this review has summarized the design and application of PROTACs developed by using existing small-molecule inhibitors in the field of cancer, based on the top five cancers with the highest incidence rate in China, with the aim of giving inspiration to new drug researchers, expanding the use of small-molecule targeted inhibitors, and breaking through the selection of drugs that are difficult to become drug sites.
Key words: Proteolysis-targeting chimaeras    Protein degration    Cancer    Ubiquitin-proteasome system
收稿日期: 2023-05-28 出版日期: 2024-04-03
ZTFLH:  Q814  
基金资助: 四川省中医药管理局团队项目(2022C010);四川省中医药管理局重点项目(2021ZD005);四川省中医药管理局重点项目(2021ZD018);四川省应急重大项目(2021XYCZ008)
通讯作者: **电子信箱:tanrui@swjtu.edu.cn   
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引用本文:

李婧绮, 吴定宇, 谭睿. 肿瘤靶向抑制剂的PROTACs设计及在抗肿瘤新药开发中的应用*[J]. 中国生物工程杂志, 2024, 44(2/3): 94-111.

LI Jingqi, WU Dingyu, TAN Rui. PROTACs’ Design of Tumor-targeting Inhibitors and Their Use in the Development of New Anti-tumor Drugs. China Biotechnology, 2024, 44(2/3): 94-111.

链接本文:

https://manu60.magtech.com.cn/biotech/CN/10.13523/j.cb.2305045    或    https://manu60.magtech.com.cn/biotech/CN/Y2024/V44/I2/3/94

图1  PROTACs作用原理图
招募E3泛素连接酶名称 配体名称 配体结构 参考文献
VHL VH032 [9]
CRBN Thalidomide [10]
cIAP1 GDC-0152 [11]
MDM2 Nutlin-3 [12]
表1  常见E3连接酶配体结构
连接体类型 连接体结构 参考文献
聚乙二醇类 [13]
氮杂环类 [14]
饱和烷基类 [15]
不饱和烷基类 [16]
新型 [17]
表2  常见连接体结构
PROTACs
名称		 靶蛋白 PROTACs结构 POI
配体来源		 肺癌类型 作用通路 参考
文献
- EGFR Gefitinib NSCLC PI3K-AKT [21]
YF135 KRAS MRTX849 NSCLC RAS-RAF-
MEK-ERK		 [24]
SIAIS117 ALK Brigatinib NSCLC、
SCLC		 PI3K-AKT、
STAT3		 [25]
DT2216 BCL-XL ABT263 NSCLC、
SCLC		 - [26]
ARV-825 BET(BRD4) OTX015 NSCLC Myc [27]
- SOS1 BI 1701963 NSCLC RAS-RAF-
MEK-ERK		 [28]
D-PROTAC FAK Defactinib NSCLC PI3K-AKT [29]
SJF-0628 BRAF Vemurafenib NSCLC RAS-RAF-
MEK-ERK		 [30]
SD-36 STAT3 SI-109 - STAT3、Myc [31]
SHP2-D26 SHP2 Compound 5 NSCLC RAS-RAF-
MEK-ERK、
PI3K-AKT		 [32]
表3  肺癌相关PROTACs
PROTACs
名称		 靶蛋白 PROTACs结构 POI
配体来源		 作用通路 参考
文献
A1874 BRD4 JQ1 Myc [34-
35]
- CDK9 Aminopyrazole
analog		 CDK9-
NELF/DSIF		 [37]
P4B BRAF(V600E) BI 882370 RAS-RAF-
MEK-ERK		 [38]
SK-575 PARP1 olaparib PARP1-CycT1 [15]
NR-7h P38 PH-797804 JNK/P38 MAPK [39]
MS432 MEK1/2 PD0325901 RAS-RAF-
MEK-ERK		 [40]
ERK-
CLIPTAC		 BRD4、 ERK1/2 ERK1/2
inhibitor		 RAS-RAF-
MEK-ERK		 [41]
CG416 TRKA/C GNF-8625 PLC-γ1 [42]
- HDAC1/2/3 CI-994 - [43]
- PDEδ Deltazinone RAS-RAF-
MEK-ERK		 [44]
表4  结直肠癌相关PROTACs
PROTACs
名称		 靶蛋白 PROTACs结构 POI配体来源 作用通路 参考
文献
PRO-6E c-MET Crizotinib RAS-RAF-
MEK-ERK、
Myc		 [47]
P7 VEGFR-2 W27 VEGF-
VEGFR2		 [49]
SDL-1 STAT3 S3I-201 STAT3 [50]
CH7C4 HER2 Tucatinib PI3K-AKT、
RAS-RAF-
MEK-ERK		 [5]
ARV-825 BRD4 OTX015 Myc-Targets、
G2M-
Checkpoint		 [51]
表5  胃癌相关PROTACs
PROTACs
名称		 靶蛋白 PROTACs结构 POI配体来源 作用通路 参考
文献
BETd-260 BET HJB-97 Myc [54]
ARV-771 BET JQ1 RAS-RAF-
MEK-ERK、
JNK/P38 MAPK		 [55]
- EGFR Dacomitinib PI3K-AKT、
RAS-RAF-
MEK-ERK		 [56]
BI-3663 PTK2 BI-4464 - [57]
- MDM2 Ursolic acid PUMA-P53-
P21		 [53]
表6  肝癌相关PROTACs
PROTACs
名称		 靶蛋白 PROTACs结构 POI
配体来源		 乳腺癌类型 作用通路 参考
文献
ERD-308 ERα Raloxifene ER+ ER [60]
CH7C4 HER2 Tucatinib HER2+ PI3K-AKT、
RAS-RAF-
MEK-ERK		 [5]
THAL-SNS-
032		 CDK9 SNS-032 ER/HER2+
HER2+		 CDK9-
pTEFb		 [62]
- CD12/CD13 Compound 3 TNBC DNA
damage、
apoptosis		 [63]
YX-02-030 MDM2 RG7112D TNBC P53 [64]
NN3 PARP1 Niraparib TNBC P53、
PARP1-
GPX4		 [65]
- eEF2K A484954 TNBC AMPK [66]
SGK3-
PROTACs1		 SGK3 308-R ER+ PI3K-AKT-
mTOR		 [67]
- TrkC Dasatinib TNBC - [68]
BP3 HSP90 BIIB021 TNBC及
ER+		 AKT、P53 [69]
SNIPER
(TACC3)-1		 TACC3 KHS101&
KHS108		 ER+ - [70]
MS8815 EZH2 EPZ-6438 TNBC Myc [71]
- AR Enzalutamide TNBC AR [72]
MZ1 BET JQ1 TNBC DNA
damage、
apoptosis		 [73]
表7  乳腺癌相关PROTACs
图2  FOXM1-PROTAC结构图
PROTACs名称 所处临床阶段
ARV-471 III期
ARV-110 III期
ARV-766 II期
CFT-7455 II期
ARV-766 II期
AC0682 I期
NX-2127 I期
HSK29116 I期
BGB-16673 I期
DT2216 I期
KT-474 I期
KT-333 I期
KT-413 I期
NX-5948 I期
FHD-609 I期
CG001419 I期
CFT8634 I期
表8  进入临床研究的PROTACs
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