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J Zhejiang Univ (Med Sci)  2020, Vol. 49 Issue (1): 1-19    DOI: 10.3785/j.issn.1008-9292.2020.02.21
    
Targeting Cullin-RING E3 ligases for anti-cancer therapy: efforts on drug discovery
YU Qing1,2(),XIONG Xiufang1,2,SUN Yi1,2,*()
1. Cancer Institute, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
2. Department of Translational Medicine, Zhejiang University, Hangzhou 310029, China
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Abstract  

Cullin-RING E3 ligases (CRLs) are the major components of ubiquitin-proteasome system, responsible for ubiquitylation and subsequent degradation of thousands of cellular proteins. CRLs play vital roles in the regulation of multiple cellular processes, including cell cycle, cell apoptosis, DNA replication, signalling transduction among the others, and are frequently dysregulated in many human cancers. The discovery of specific neddylation inhibitors, represented by MLN4924, has validated CRLs as promising targets for anti-cancer therapies with a growing market. Recent studies have focused on the discovery of the CRLs inhibitors by a variety of approaches, including high through-put screen, virtual screen or structure-based drug design. The field is, however, still facing the major challenging, since CRLs are a large multi-unit protein family without typical active pockets to facilitate the drug design, and enzymatic activity is mainly dependent on undruggable protein-protein interactions and dynamic conformation changes. Up to now, most reported CRLs inhibitors are aiming at targeting the F-box family proteins (e.g., SKP2, β-TrCP and FBXW7), the substrate recognition subunit of SCF E3 ligases. Other studies reported few small molecule inhibitors targeting the UBE2M-DCN1 interaction, which specifically inhibits CRL3/CRL1 by blocking the cullin neddylation. On the other hand, several CRL activators have been reported, such as plant auxin and immunomodulatory imide drugs, thalidomide. Finally, proteolysis-targeting chimeras (PROTACs) has emerged as a new technology in the field of drug discovery, specifically targeting the undruggable protein-protein interaction. The technique connects the small molecule that selectively binds to a target protein to a CRL E3 via a chemical linker to trigger the degradation of target protein. The PROTAC has become a hotspot in the field of E3-ligase-based anti-cancer drug discovery.



Key wordsUbiquitin-protein ligases      Antineoplastic/therapeutic      Cullin-RING E3 ligases      Enzyme inhibitors      Enzyme activators      Proteolysis-targeting chimera      Review     
Received: 20 December 2019      Published: 08 June 2020
CLC:  R730.5  
Corresponding Authors: SUN Yi     E-mail: yuqing@zju.edu.cn;yisun@zju.edu.cn
Cite this article:

YU Qing, XIONG Xiufang, SUN Yi. Targeting Cullin-RING E3 ligases for anti-cancer therapy: efforts on drug discovery. J Zhejiang Univ (Med Sci), 2020, 49(1): 1-19.

URL:

http://www.zjujournals.com/med/10.3785/j.issn.1008-9292.2020.02.21     OR     http://www.zjujournals.com/med/Y2020/V49/I1/1


靶向Cullin-RING E3泛素连接酶的抗肿瘤策略及相关药物研发进展

Cullin-RING E3泛素连接酶(CRL)是泛素-蛋白酶体系统的重要组分,参与催化蛋白质的泛素化,促进随后的蛋白质降解,从而影响细胞周期、细胞凋亡、DNA复制、信号转导等多种细胞生理活动,且在多种肿瘤细胞中异常活化。以MLN4924为代表的拟素化抑制剂的成功研发有力地证实了CRL是可行的抗肿瘤靶点,具有很好的药物研发潜力。近年来,不断有新的研究通过高通量筛选、基于计算机辅助的虚拟筛选或基于结构的药物设计技术寻找特异的CRL抑制剂,但由于CRL复合物具有多种亚单位,呈蛋白-蛋白相互作用和多变的蛋白构象,缺乏典型的小分子药物结合位点等特性,其相关药物研发仍面临巨大挑战。截至目前,CRL小分子抑制剂主要以研究最为透彻的SCF泛素连接酶复合体的底物识别亚基F-box蛋白家族为靶点。此外,也发现数个通过靶向UBE2M-DCN1相互作用,特异性阻断CRL3/CRL1拟素化,从而抑制CRL3/CRL1泛素连接酶活性的小分子化合物。另一方面,也有CRL激动剂的报道,主要见于植物生长素吲哚乙酸和免疫调节性酰亚胺类药物。此外,靶蛋白水解嵌合体(PROTAC)是一项靶向蛋白-蛋白相互作用的新技术,其通过特异性小分子抑制剂链接一个CRL E3泛素连接酶来精确降解特定促癌靶蛋白,已成为近年来利用E3泛素连接酶设计抗肿瘤靶向药物的热点。


关键词: 泛素蛋白连接酶类,  抗肿瘤/治疗学,  Cullin-RING E3泛素连接酶,  酶抑制剂,  酶激动剂类,  靶蛋白水解嵌合体,  综述 
Fig 1 The ubiquitin-proteasome system with focus on CRL E3 ligase and the neddylation of cullins leading to activation of Cullin-RING E3 ubiquitin ligases
Fig 2 The components of cullin-RING E3 ligases and known substrates
Fig 3 Inhibit or activate Cullin-RING E3 ubiquitin ligases (CRL) in a context dependent manner for anti-cancer applications
名称 靶蛋白 影响的PPI 对细胞中主要底物的影响 研发途径 其他说明 参考文献
“—”无相关资料.PPI:蛋白-蛋白相互作用; FRET:荧光共振能量转移; TR-FRET:时间分辨荧光共振能量转移; HTRF:均相时间分辨荧光.
CRL E3抑制剂
Compound A SKP2 SKP2:SKP1 p27、p21、p53蛋白积累 高通量筛选 在多发性骨髓瘤细胞中可增加细胞对硼替佐米敏感性 [54]
C1、C2、C16、C20 SKP2 SKP2:Cks1 p27蛋白积累 基于配体分子的虚拟筛选 首次通过虚拟筛选获得阻断SKP2-底物相互作用的小分子 [55]
Compound #25 SKP2 SKP2:SKP1 p27、p21、Notch1蛋白积累 基于受体结构的虚拟筛选 在前列腺癌细胞系PC3中可降低肿瘤干细胞比例 [56]
NSC689857、NSC681152 SKP2 SKP2:Cks1 p27蛋白积累 基于AlphaScreen的高通量筛选 同时具有络氨酸激酶抑制活性 [57]
Eroflorin β-TrCP β-TrCP:PDCD4 PDCD4蛋白积累 基于荧光素酶报告系统的高通量筛选 天然产物 [58]
SCF-I2 Cdc4(酵母FBXW7) Cdc4:Sic1 Sic1蛋白泛素化水平降低 基于荧光偏振的高通量筛选(酵母) 第一个特异性靶向WD40结构域的小分子变构抑制剂 [59]
Suramin CUL1 CUL1:CDC34 p27、CDT1蛋白积累 基于FRET的高通量筛选 天然产物;基于FRET的K48双泛素化报告系统 [60]
SMER3 Met30(酵母F-box) Met30:Skp1 Met4蛋白泛素化水平降低 基于化学遗传学的高通量筛选(酵母) 小分子雷帕霉素增强剂 [61]
NAcM-HIT、NAcM-OPT等 DCN1 DCN1:UBE2M p27、Nrf2蛋白积累 基于TR-FRET的高通量筛选 特异性抑制CRL3/CRL1活性 [62-65]
DI-591、DI-404 DCN1 DCN1:UBE2M Nrf2蛋白积累 基于结构的药物设计 特异性抑制CRL3活性 [66-67]
WS-383 DCN1 DCN1:UBE2M p21、p27、Nrf2蛋白积累 基于HTRF的高通量筛选 特异性抑制CRL3/CRL1活性 [68]
DC-2、DC-1 DCN1 DCN1:UBE2M Nrf2蛋白积累 基于HTRF和荧光偏振的高通量筛选 特异性抑制CRL3活性 [69]
CRL E3激动剂
Auxin TIR1(植物) TIR1:Aux/IAA 促进Aux/IAA降解 非创新药研发 [70-71]
Thalidomide、Lenalidomide、Pomalidomide CRL4-CRBN CRBN:IKZF1/3 促进IKZF1和IKZF3降解 非创新药研发 [72-75]
NRX-1532、NRX-252262 β-catenin/ β-TrCP β-catenin:β-TrCP 促进S37A突变β-catenin降解 基于荧光偏振的高通量筛选 [76]
Oridonin FBXW7 尚不明确 促进c-Myc降解 非创新药研发 [77]
Tab 1 Reported inhibitors and activators of Cullin-RING E3 ligases
Fig 4 Small-molecule inhibitors targeting Cullin-RING E3 ligases
Fig 5 Small molecules targeting UBE2M-DCN1 interaction to block neddylation of cullin-3 and cullin-1
Fig 6 "Molecular glue" mechanism in activators of Cullin-RING E3 ligase
Fig 7 Mechanism of proteolysis-targeting chimeras
名称 结构 识别的E3 靶蛋白 其他说明 参考文献
PROTAC-1 SCFβ-TrCP MetAp-2 第一个PROTAC [106]
PROTAC-4 CRL2VHL FKBP12F36V 第一个可进入细胞的PROTAC [107]
TrkAPPFRS2α CRL2VHL FRS2α 第一个磷酸化的PROTAC [108]
SARM-nutlin PROTAC MDM2 雄激素受体 第一个全小分子的PROTAC [109]
ARV-110 暂无 暂无 雄激素受体 第一个进入临床试验的PROTAC [110]
Tab 2 Representative proteolysis-targeting chimeras (PROTACs) and related technologies
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