药学学报

PRMTs	Expression	Substrate	Outcome	Relevant pathway	Ref.
PRMT1	High	hnRNPK	Cancer proliferation, migration and invasion	Methylate hnRNPK and regulate gene transcription	[12]
SMARCA4	Cancer proliferation, migration and poor prognosis	Activate EGFR signaling pathway	[13]
NONO	Cancer proliferation, migration and invasion	Methylate NONO	[14]
PGK1	Cancer proliferation	Enhance glycolysis	[15]
RIP3	Prevent immune escape	Block necroptosis	[16]
PRMT3	High	HIF1α	Tumorigenesis	Activate HIF1α/VEGFA signaling pathway	[17]
c-MYC	Cancer proliferation, migration and invasion	Inhibit the ubiquitination of c-MYC and stabilize c-MYC	[18]
PRMT4	High	p300-c-Myc-Max	Cancer proliferation	Degrade ST7	[19]
RPF2	Cancer invasion, metastasis and drug resistance	Induce EMT by activating AKT/GSK-3β signaling pathway; up-regulate expression of ABCB1 by regulating CARM1-MYCN pathway	[20, 21]
RPIA	Tumor growth	Enhance PPP	[22]
ACSL4	Tumor growth	Induce ubiquitylation of ACSL4 and inhibit ferroptosis	[23]
PRMT5	High	LDHA	Cancer proliferation	Enhance glycolysis	[24]
EZH2	Cancer progression and poor prognosis	Repress expression of CDKN2B	[25]
YBX1, PKCι	Cancer proliferation	Activate NF-κB signaling pathway	[26, 27]
Smad4	Cancer metastasis	Activate TGF-β signaling pathway and induce EMT	[28]
ZEB2-TWIST1-NuRD	Cancer metastasis	Suppress transcription of E-cadherin and induce EMT	[29]
MCM7	Cancer proliferation, migration and invasion	Bind with MCM7 to enhance MCM7 oncogenic functions	[30]
PRMT6	High	CDKN2B, CCNG1	Tumorigenesis and cancer progression	Repress transcription of cell cycle regulators	[31]
PRMT7	High	hnRNPA1	Tumor growth	Methylate hnRNPA1	[32]

PRMTs

Expression

Substrate

Outcome

Relevant pathway

Ref.

PRMT1

High

hnRNPK

Cancer proliferation, migration and invasion

Methylate hnRNPK and regulate gene transcription

[12]

SMARCA4

Cancer proliferation, migration and poor prognosis

Activate EGFR signaling pathway

[13]

NONO

Cancer proliferation, migration and invasion

Methylate NONO

[14]

PGK1

Cancer proliferation

Enhance glycolysis

[15]

RIP3

Prevent immune escape

Block necroptosis

[16]

PRMT3

High

HIF1α

Tumorigenesis

Activate HIF1α/VEGFA signaling pathway

[17]

c-MYC

Cancer proliferation, migration and invasion

Inhibit the ubiquitination of c-MYC and stabilize c-MYC

[18]

PRMT4

High

p300-c-Myc-Max

Cancer proliferation

Degrade ST7

[19]

RPF2

Cancer invasion, metastasis and drug resistance

Induce EMT by activating AKT/GSK-3β signaling pathway; up-regulate expression of ABCB1 by regulating CARM1-MYCN pathway

[20, 21]

RPIA

Tumor growth

Enhance PPP

[22]

ACSL4

Tumor growth

Induce ubiquitylation of ACSL4 and inhibit ferroptosis

[23]

PRMT5

High

LDHA

Cancer proliferation

Enhance glycolysis

[24]

EZH2

Cancer progression and poor prognosis

Repress expression of CDKN2B

[25]

YBX1, PKCι

Cancer proliferation

Activate NF-κB signaling pathway

[26, 27]

Smad4

Cancer metastasis

Activate TGF-β signaling pathway and induce EMT

[28]

ZEB2-TWIST1-NuRD

Cancer metastasis

Suppress transcription of E-cadherin and induce EMT

[29]

MCM7

Cancer proliferation, migration and invasion

Bind with MCM7 to enhance MCM7 oncogenic functions

[30]

PRMT6

High

CDKN2B, CCNG1

Tumorigenesis and cancer progression

Repress transcription of cell cycle regulators

[31]

PRMT7

High

hnRNPA1

Tumor growth

Methylate hnRNPA1

[32]

PRMTs	Expression	Substrate	Outcome	Relevant pathway	Ref.
PRMT1	High	hnRNPK	Cancer proliferation, migration and invasion	Methylate hnRNPK and regulate gene transcription	[12]
SMARCA4	Cancer proliferation, migration and poor prognosis	Activate EGFR signaling pathway	[13]
NONO	Cancer proliferation, migration and invasion	Methylate NONO	[14]
PGK1	Cancer proliferation	Enhance glycolysis	[15]
RIP3	Prevent immune escape	Block necroptosis	[16]
PRMT3	High	HIF1α	Tumorigenesis	Activate HIF1α/VEGFA signaling pathway	[17]
c-MYC	Cancer proliferation, migration and invasion	Inhibit the ubiquitination of c-MYC and stabilize c-MYC	[18]
PRMT4	High	p300-c-Myc-Max	Cancer proliferation	Degrade ST7	[19]
RPF2	Cancer invasion, metastasis and drug resistance	Induce EMT by activating AKT/GSK-3β signaling pathway; up-regulate expression of ABCB1 by regulating CARM1-MYCN pathway	[20, 21]
RPIA	Tumor growth	Enhance PPP	[22]
ACSL4	Tumor growth	Induce ubiquitylation of ACSL4 and inhibit ferroptosis	[23]
PRMT5	High	LDHA	Cancer proliferation	Enhance glycolysis	[24]
EZH2	Cancer progression and poor prognosis	Repress expression of CDKN2B	[25]
YBX1, PKCι	Cancer proliferation	Activate NF-κB signaling pathway	[26, 27]
Smad4	Cancer metastasis	Activate TGF-β signaling pathway and induce EMT	[28]
ZEB2-TWIST1-NuRD	Cancer metastasis	Suppress transcription of E-cadherin and induce EMT	[29]
MCM7	Cancer proliferation, migration and invasion	Bind with MCM7 to enhance MCM7 oncogenic functions	[30]
PRMT6	High	CDKN2B, CCNG1	Tumorigenesis and cancer progression	Repress transcription of cell cycle regulators	[31]
PRMT7	High	hnRNPA1	Tumor growth	Methylate hnRNPA1	[32]

PRMTs

Expression

Substrate

Outcome

Relevant pathway

Ref.

PRMT1

High

hnRNPK

Cancer proliferation, migration and invasion

Methylate hnRNPK and regulate gene transcription

[12]

SMARCA4

Cancer proliferation, migration and poor prognosis

Activate EGFR signaling pathway

[13]

NONO

Cancer proliferation, migration and invasion

Methylate NONO

[14]

PGK1

Cancer proliferation

Enhance glycolysis

[15]

RIP3

Prevent immune escape

Block necroptosis

[16]

PRMT3

High

HIF1α

Tumorigenesis

Activate HIF1α/VEGFA signaling pathway

[17]

c-MYC

Cancer proliferation, migration and invasion

Inhibit the ubiquitination of c-MYC and stabilize c-MYC

[18]

PRMT4

High

p300-c-Myc-Max

Cancer proliferation

Degrade ST7

[19]

RPF2

Cancer invasion, metastasis and drug resistance

Induce EMT by activating AKT/GSK-3β signaling pathway; up-regulate expression of ABCB1 by regulating CARM1-MYCN pathway

[20, 21]

RPIA

Tumor growth

Enhance PPP

[22]

ACSL4

Tumor growth

Induce ubiquitylation of ACSL4 and inhibit ferroptosis

[23]

PRMT5

High

LDHA

Cancer proliferation

Enhance glycolysis

[24]

EZH2

Cancer progression and poor prognosis

Repress expression of CDKN2B

[25]

YBX1, PKCι

Cancer proliferation

Activate NF-κB signaling pathway

[26, 27]

Smad4

Cancer metastasis

Activate TGF-β signaling pathway and induce EMT

[28]

ZEB2-TWIST1-NuRD

Cancer metastasis

Suppress transcription of E-cadherin and induce EMT

[29]

MCM7

Cancer proliferation, migration and invasion

Bind with MCM7 to enhance MCM7 oncogenic functions

[30]

PRMT6

High

CDKN2B, CCNG1

Tumorigenesis and cancer progression

Repress transcription of cell cycle regulators

[31]

PRMT7

High

hnRNPA1

Tumor growth

Methylate hnRNPA1

[32]

Drug	Target	Mechanism	Ref.
MS023	PRMT1	Induce cancer differentiation and inhibit proliferation	[64]
A peptide inhibitor	PRMT1	Induce apoptosis and autophagy	[65]
Oxicam analogues	PRMT1/PRMT5	Metabolic reprogramming	[67]
SGC2085	CARM1	Inhibit cancer proliferation	[68, 69]
EZM2302	CARM1	Induce ferroptosis and sensitize CRC cells to anti-PD-1 immunotherapy	[23, 70]
AMI-1	PRMT5	Down-regulate expression of eIF4E and FGFR3; promote apoptosis	[72]
GSK3235025	PRMT5	Inhibit tumor growth; cell cycle arrest	[56, 73]
GSK3203591	PRMT5	Suppress alternative splicing regulated by PRMT5	[32]
PR5-LL-CM01	PRMT5	Inhibit NF-κB pathway and tumor growth	[74]
Ribavirin	PRMT5	Reduce expression of eIF4E; cell cycle arrest	[75]
Tadalafil	PRMT5	Inhibit glycolysis; sensitizes CRC cells to 5-FU	[24]
SGC3027	PRMT7	Inhibit tumor growth	[63, 76, 77]

Drug

Target

Chemical structure

Mechanism

Ref.

MS023

PRMT1

Induce cancer differentiation and inhibit proliferation

[64]

A peptide inhibitor

PRMT1

Induce apoptosis and autophagy

[65]

Oxicam analogues

PRMT1/PRMT5

Metabolic reprogramming

[67]

SGC2085

CARM1

Inhibit cancer proliferation

[68, 69]

EZM2302

CARM1

Induce ferroptosis and sensitize CRC cells to anti-PD-1 immunotherapy

[23, 70]

AMI-1

PRMT5

Down-regulate expression of eIF4E and FGFR3; promote apoptosis

[72]

GSK3235025

PRMT5

Inhibit tumor growth; cell cycle arrest

[56, 73]

GSK3203591

PRMT5

Suppress alternative splicing regulated by PRMT5

[32]

PR5-LL-CM01

PRMT5

Inhibit NF-κB pathway and tumor growth

[74]

Ribavirin

PRMT5

Reduce expression of eIF4E; cell cycle arrest

[75]

Tadalafil

PRMT5

Inhibit glycolysis; sensitizes CRC cells to 5-FU

[24]

SGC3027

PRMT7

Inhibit tumor growth

[63, 76, 77]

Drug	Target	Mechanism	Ref.
MS023	PRMT1	Induce cancer differentiation and inhibit proliferation	[64]
A peptide inhibitor	PRMT1	Induce apoptosis and autophagy	[65]
Oxicam analogues	PRMT1/PRMT5	Metabolic reprogramming	[67]
SGC2085	CARM1	Inhibit cancer proliferation	[68, 69]
EZM2302	CARM1	Induce ferroptosis and sensitize CRC cells to anti-PD-1 immunotherapy	[23, 70]
AMI-1	PRMT5	Down-regulate expression of eIF4E and FGFR3; promote apoptosis	[72]
GSK3235025	PRMT5	Inhibit tumor growth; cell cycle arrest	[56, 73]
GSK3203591	PRMT5	Suppress alternative splicing regulated by PRMT5	[32]
PR5-LL-CM01	PRMT5	Inhibit NF-κB pathway and tumor growth	[74]
Ribavirin	PRMT5	Reduce expression of eIF4E; cell cycle arrest	[75]
Tadalafil	PRMT5	Inhibit glycolysis; sensitizes CRC cells to 5-FU	[24]
SGC3027	PRMT7	Inhibit tumor growth	[63, 76, 77]

Drug

Target

Chemical structure

Mechanism

Ref.

MS023

PRMT1

Induce cancer differentiation and inhibit proliferation

[64]

A peptide inhibitor

PRMT1

Induce apoptosis and autophagy

[65]

Oxicam analogues

PRMT1/PRMT5

Metabolic reprogramming

[67]

SGC2085

CARM1

Inhibit cancer proliferation

[68, 69]

EZM2302

CARM1

Induce ferroptosis and sensitize CRC cells to anti-PD-1 immunotherapy

[23, 70]

AMI-1

PRMT5

Down-regulate expression of eIF4E and FGFR3; promote apoptosis

[72]

GSK3235025

PRMT5

Inhibit tumor growth; cell cycle arrest

[56, 73]

GSK3203591

PRMT5

Suppress alternative splicing regulated by PRMT5

[32]

PR5-LL-CM01

PRMT5

Inhibit NF-κB pathway and tumor growth

[74]

Ribavirin

PRMT5

Reduce expression of eIF4E; cell cycle arrest

[75]

Tadalafil

PRMT5

Inhibit glycolysis; sensitizes CRC cells to 5-FU

[24]

SGC3027

PRMT7

Inhibit tumor growth

[63, 76, 77]

靶向蛋白质精氨酸甲基转移酶抗结直肠癌小分子药物研究进展

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张佳欣 , 王茜 , 张瑞雪 , 刘东辉 , 孔德新 ^* , 邱玉玲 ^*

药学学报 | 综述 2026,61(1): 109-121

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药学学报 |综述 2026 , 61 (1) : 109 -121

靶向蛋白质精氨酸甲基转移酶抗结直肠癌小分子药物研究进展

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张佳欣, 王茜, 张瑞雪, 刘东辉, 孔德新^*, 邱玉玲^*

作者信息

天津医科大学药学院, 天津 300070

通讯作者:

孔德新, E-mail: kongdexin@tmu.edu.cn

邱玉玲, E-mail: qiuyuling@tmu.edu.cn

作者简介:

作者贡献:

张佳欣负责撰写及修改综述; 王茜负责提供撰写思路及论文修改; 张瑞雪负责文章的完善; 刘东辉负责文献的查询; 孔德新、邱玉玲负责文章选题、文章指导与修改。

Research progress of small molecular drugs targeting protein arginine methyltransferases in colorectal cancer therapy

Jia-xin ZHANG, Qian WANG, Rui-xue ZHANG, Dong-hui LIU, De-xin KONG^*, Yu-ling QIU^*

Affiliations

School of Pharmacy, Tianjin Medical University, Tianjin 300070, China

出版时间: 2026-01-12 doi: 10.16438/j.0513-4870.2025-0298

文章导航

摘要

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蛋白质精氨酸甲基化是一种重要的翻译后修饰和表观遗传调节机制。在哺乳动物细胞中, 蛋白质精氨酸甲基转移酶(protein arginine methyltransferases, PRMTs)催化蛋白质精氨酸残基发生甲基化修饰。迄今为止, 已在哺乳动物及植物中发现11种PRMTs。PRMTs可催化甲基从S-腺苷-L-甲硫氨酸转移到底物蛋白质精氨酸的胍基氮原子上, 生成精氨酸甲基化蛋白, 从而在DNA损伤修复、RNA剪接加工、转录、翻译、细胞信号转导、细胞周期调控、蛋白质-蛋白质相互作用、蛋白质-核酸相互作用等生物学过程中发挥重要作用。PRMTs所介导的蛋白质精氨酸甲基化失调与癌症的发生、发展密切相关。因此, 以PRMTs为靶点的抗癌药物研发也成为肿瘤治疗领域的研究热点。本文综述了PRMTs在结直肠癌病理过程中的作用及分子机制, 并介绍了以PRMTs为靶点的抗结直肠癌小分子药物研究进展, 旨在为天然产物来源靶向PRMTs抗结直肠癌小分子药物的研发提供理论基础和重要线索。

关键词

蛋白质精氨酸甲基转移酶 / 蛋白质精氨酸甲基化 / 结直肠癌 / 小分子药物 / 靶向治疗

Abstract

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Protein arginine methylation is an important post-translational modification and epigenetic regulation mechanism. In mammalian cells, protein arginine methyltransferases (PRMTs) catalyze the methylation of protein arginine residues. Eleven PRMTs have been found in mammals and plants to date. PRMTs catalyze the transfer of methyl groups from S-adenosyl-L-methionine to the guanidinium nitrogen atom of arginine residues in substrates to produce arginine methylated proteins, thus playing key roles in the control of many biological processes such as DNA damage repair, RNA splicing processing, transcription, translation, cell signal transduction, cell cycle regulation, protein-protein interactions, protein-nucleic acid interactions. Dysregulation of protein arginine methylation mediated by PRMTs is closely related to the occurrence and development of cancer. Therefore, the development of anticancer drugs targeting PRMTs has also become a research hotspot in the field of cancer treatment. This paper reviews the role and molecular mechanisms of PRMTs in the pathological process of colorectal cancer, and introduces the research progress of small molecule drugs targeting PRMTs in colorectal cancer therapy, aiming to provide a theoretical basis and important clues for the development of small molecule drugs isolating from natural products and targeting at PRMTs in colorectal cancer treatment.

Key words

protein arginine methyltransferase / protein arginine methylation / colorectal cancer / small molecule drug / targeted therapy

引用本文

张佳欣, 王茜, 张瑞雪, 刘东辉, 孔德新, 邱玉玲. 靶向蛋白质精氨酸甲基转移酶抗结直肠癌小分子药物研究进展. 药学学报, 2026 , 61 (1) : 109 -121 . DOI: 10.16438/j.0513-4870.2025-0298

Jia-xin ZHANG, Qian WANG, Rui-xue ZHANG, Dong-hui LIU, De-xin KONG, Yu-ling QIU. Research progress of small molecular drugs targeting protein arginine methyltransferases in colorectal cancer therapy[J]. Acta Pharmaceutica Sinica, 2026 , 61 (1) : 109 -121 . DOI: 10.16438/j.0513-4870.2025-0298

正文

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结直肠癌(colorectal cancer, CRC)是世界上第3大常见的恶性肿瘤, 也是全球第二大癌症死亡原因, 其死亡率占癌症相关死亡总数的9.3%^[1]。数据统计显示, CRC发病率已呈年轻化趋势^[2]。此外, 尽管早期CRC患者的5年无病生存率为91%, 而晚期CRC生存率则显著降低, 仅有14%^[2]。这表明CRC已成为一个尤为严峻的全球性健康问题。CRC早期诊断和有效治疗药物的研发成为当前重要的课题。CRC的发生是多种因素导致结肠或直肠中的细胞异常增殖, 且随着时间推移最终癌变致病^[3]。众所周知, 除遗传性因素外, 非遗传性因素(例如肥胖、缺乏锻炼、吸烟、饮酒和不健康饮食等)也是引起CRC的风险因素^[4]。由这些风险因素引起的基因突变和表观遗传学改变是CRC发病的核心驱动力^[5]。近年来, 以蛋白精氨酸甲基化修饰为主的表观遗传学研究是CRC研究的热点领域之一^[6]。

蛋白质精氨酸甲基转移酶(protein arginine methyltransferases, PRMTs)负责催化底物蛋白质的精氨酸残基发生甲基化修饰^[7]。PRMTs通过3种方式催化精氨酸甲基化, 分别是单甲基化(monomethyl arginine, MMA)、不对称二甲基化(asymmetric dimethylarginine, ADMA)和对称二甲基化(symmetrical dimethylarginine, SDMA)。根据以上3种不同催化方式及产生甲基化精氨酸的类型将PRMTs分为3类: Ⅰ型PRMTs包括PRMT1、PRMT2、PRMT3、PRMT4、PRMT6、PRMT8、AtPRMT10和AtPRMT11, 可催化底物形成MMA和ADMA; Ⅱ型PRMTs有PRMT5和PRMT9, 催化底物形成MMA和SDMA; Ⅲ型PRMTs只有PRMT7, 催化底物形成MMA^[7-9]。另外, Ⅰ型PRMTs中的AtPRMT10及AtPRMT11存在于植物拟南芥中, 其中AtPRMT11与哺乳动物中PRMT1高度相似^{[8, 9]}。但目前对AtPRMT10和AtPRMT11的作用机制及功能研究较少。

PRMTs催化甲基从S-腺苷-L-甲硫氨酸(S-adenosyl-L-methionine, SAM)转移到组蛋白或非组蛋白的精氨酸残基上而发挥翻译后修饰作用, 组蛋白精氨酸残基的甲基化修饰对基因转录活性有双向调控作用, 例如, PRMT1/3催化形成的组蛋白H4第3位精氨酸不对称二甲基化(H4R3me2a)可作为转录激活的表观遗传标志, 而PRMT5介导的同一位点对称二甲基化(H4R3me2s)则与转录抑制密切相关^[7]。此外, PRMTs亦可催化非组蛋白底物甲基化, 例如, PRMT1甲基化泛素相关蛋白2样(ubiquitin-associated protein 2-like, UBAP2L)精氨酸的RGG/RG结构域, 该甲基化对于中期染色体的正确对齐和准确分布至关重要^[10]。PRMTs通过催化组蛋白和非组蛋白精氨酸残基发生甲基化, 从表观遗传学层面上调控众多细胞生命活动过程, 包括剪接、转录、翻译、信号转导、DNA损伤修复、调节细胞周期以及蛋白质-蛋白质相互作用等^[7]。近年来, 研究发现PRMTs也参与调控炎症和免疫反应、细胞代谢、细胞凋亡逃逸和上皮-间充质转化等恶性肿瘤的病理进程, 因此, PRMTs与癌症的发生发展密切相关, 以PRMTs为靶点的抗癌药物研发也成为肿瘤治疗领域的研究热点^[7]。

1　蛋白质精氨酸甲基转移酶在结直肠癌中的作用及分子机制

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蛋白质精氨酸甲基化是蛋白质翻译后修饰的一个重要类型, 通过调节蛋白质功能参与调节细胞的增殖和存活^{[6, 11]}。PRMTs作为这一过程中的重要调控蛋白, 在CRC的病理过程中发挥了重要作用。表1^[12-32]概括了常见的各类型PRMTs在CRC中的作用及分子机制。

1.1　PRMT1

PRMT1是蛋白质精氨酸甲基转移酶家族中最主要的酶, 属于Ⅰ型PRMT家族蛋白。在近90%的哺乳动物细胞中, PRMT1能催化蛋白质精氨酸发生单甲基化和不对称二甲基化^[33]。Taniguchi等^[34]发现, 一氧化氮可诱导PRMT1在半胱氨酸119残基处的S-亚硝基化, 从而减弱PRMT1的酶活性, 抑制ADMA生成, 并达到类似于敲低PRMT1或应用PRMT1抑制剂所产生的抑制作用。PRMT1的表达或活性异常与人类癌症发生与进展密切相关^[35-38]。

PRMT1在CRC中高表达^[38], 其表达水平与CRC患者肿瘤大小、病理分期呈正相关, 与CRC患者总生存率呈负相关^[13]。研究发现, PRMT1通过催化癌蛋白甲基化参与调控CRC的发生^[12-14]。hnRNPK在CRC细胞中显著高表达, 并作为促癌基因在CRC中发挥作用, 其编码的hnRNPK蛋白是PRMT1的底物之一^[12]。PRMT1通过催化hnRNPK的精氨酸甲基化调控CKS2、PTMA、PAICS、SUV39H2、NPM1等基因的转录(这些基因与可变剪切、p53信号通路及细胞周期密切相关), 促进CRC细胞的增殖、迁移与侵袭, 介导CRC病理进程^[12]。

SWI/SNF相关、基质相关、肌动蛋白依赖性染色质调节子亚家族A成员4 (SWI/SNF related matrix-associated actin-dependent regulator of chromatin subfamily A member 4, SMARCA4)是SWI/SNF复合物的核心亚基。有报道显示, SMARCA4也能发挥致癌作用^[39-42]。作为一种主要的H4R3me2a相关蛋白, SMARCA4可与PRMT1协同促进CRC细胞增殖, 且高表达的PRMT1和SMARCA4皆与CRC不良预后相关^[13]。经PRMT1甲基化的H4R3me2a直接招募SMARCA4至TNS4、表皮生长因子受体(epidermal growth factor receptor, EGFR)启动子上, 激活转录, 并激活EGFR信号转导, 从而促进CRC细胞增殖与迁移^[13]。Zeng等^[43]发现, SMARCA4^R1157W突变一方面可促进其与H4R3me2a的结合, 增强EGFR信号转导, 另一方面还可增强SWI/SNF复合物的ATP酶活性以促进染色质募集和重塑, 最终加速CRC进展。同时抑制PRMT1和SMARCA4在体内、外皆可协同抑制SMARCA4^R1157W突变型CRC细胞生长^[43]。

含非POU结构域的八聚体结合蛋白质(non-POU domain-containing octamer-binding protein, NONO)是一种具有促癌作用的核蛋白, 在CRC患者肿瘤组织中过表达^[14]。PRMT1能特异性催化NONO上的R251位点发生不对称二甲基化, 增强NONO的致癌作用, 进而促进CRC细胞的增殖、迁移和侵袭, 目前尚无可直接靶向NONO的抗体药物或者抑制剂^[14]。研究表明, 在KRAS野生型或突变型CRC细胞中, 与NONO甲基化相关的恶性表型在敲低或抑制PRMT1后均可消除。这表明, 无论KRAS突变与否, PRMT1皆可作为NONO的替代靶点成为治疗CRC的有效策略^[14]。在影响癌细胞代谢方面, PRMT1可通过增强糖酵解促进CRC进展^[15]。PRMT1通过催化磷酸甘油酸酯激酶1 (phosphoglycerate kinase 1, PGK1)的R206甲基化增强由ERK介导PGK1的S203磷酸化, 进而增强PGK1在线粒体的定位, 并促进丙酮酸激酶磷酸化, 削弱线粒体功能, 如抑制了三羧酸循环(tricarboxylic acid cycle, TCA cycle), 增强糖酵解活性, 促进CRC细胞增殖^[15]。

尽管大量研究报道了PRMT1在CRC中起致癌作用, 但仍有部分研究提出PRMT1在抑癌方面亦发挥着积极作用^{[16, 44, 45]}。PRMT1可通过抑制坏死性凋亡发挥抗肿瘤免疫逃逸功能^[16]。Zhang等^[16]报道了在结肠癌细胞中, 受体相互作用蛋白激酶3 (receptor interacting protein kinase 3, RIP3)的R486 (或鼠源R479)位突变引起其自身甲基化缺陷、增加了肿瘤浸润髓源性免疫抑制细胞(myeloid-derived immune suppressor cells, MDSCs), 促进了坏死性凋亡, 从而激发免疫逃逸和结肠癌进展, 而过表达PRMT1能通过催化RIP3甲基化来抑制RIP1-RIP3坏死体复合物形成, 从而抑制RIP3的磷酸化并阻断坏死性凋亡信号通路, 减少MDSCs浸润, 最终抑制坏死性凋亡依赖性的免疫逃逸, 同时激发有益的免疫微环境, 抑制肿瘤生长。PRMT1在CRC细胞中的作用及分子机制如图1所示。

由此可见, PRMT1在CRC中具有抑癌和促癌的双重作用, 既可促进癌细胞增殖与迁移发挥致癌作用, 又可通过抑制肿瘤免疫逃逸而发挥抑癌作用。因此, 靶向PRMT1治疗CRC可能在杀死癌细胞的同时增加癌细胞免疫逃逸。对PRMT1在结直肠癌病理过程中发挥的作用及详细的分子机制还需要进一步深入剖析, 以PRMT1为靶点的治疗策略尚需要斟酌损益。

1.2　PRMT3

PRMT3是一种较为特殊的Ⅰ型PRMT家族成员蛋白, 多位于细胞质中, 其N端有一个C2H2锌指结构域。这一特有的锌指结构域能与其他基因的特定DNA序列相互作用, 在PRMT3与底物特异性识别中起着至关重要的作用^[46-48]。PRMT3通过催化DNA复制酶、代谢酶发生甲基化来促进肿瘤发生, 并且可以通过甲基化RNA结合蛋白增强癌细胞的化疗耐药性^[49]。有文献显示, PRMT3在CRC细胞中高表达, 它的缺失能够显著抑制结直肠癌细胞的增殖、迁移和侵袭能力, 且PRMT3的表达与CRC患者总生存期呈负相关, PRMT3的表达水平是CRC患者总生存时间的独立危险因素^{[17, 18]}。肿瘤生长过程中的重要标志之一是异常血管生成, 这是由癌细胞中促血管生成因子(如缺氧诱导因子1α, hypoxia-induced factor 1α, HIF1α)的异常表达所驱动的^[50]。Zhang等^[17]发现, HIF1α是PRMT3的底物之一, 且PRMT3介导CRC发生是HIF1α依赖性的。PRMT3通过催化HIF1α的R282甲基化抑制HIF1α的泛素化, 增强HIF1α的稳定性, 进而激活HIF1α/血管内皮生长因子A (vascular endothelial growth factor A, VEGFA)信号通路, 诱导内皮细胞增殖、迁移和血管生成, 促进肿瘤微环境中的异常血管形成, 促进肿瘤发生与进展。另外, PRMT3介导肿瘤形成与c-MYC密切相关^[18]。在CRC中, 高表达的PRMT3与c-MYC直接结合以抑制c-MYC的泛素化并上调c-MYC的表达, 促进CRC增殖、迁移与侵袭^[18]。

PRMT3在结直肠癌中呈较高的表达水平, 与结直肠癌的发生和发展密切相关, 但其详细的分子机制研究报道仍相对较少, PRMT3在CRC中的生物学功能及潜在机制仍需进一步探究。

1.3　PRMT4

PRMT4自身具有转录共激活活性, 故又称共激活相关精氨酸甲基转移酶1 (coactivator-associated arginine methyltransferase, CARM1), 主要存在于细胞核和细胞质中。CARM1能催化H3末端的17和26位精氨酸残基(H3R17和H3R26)发生甲基化, 在转录激活中发挥至关重要的作用^[51]。CARM1在CRC细胞中高表达^[52], 可与多种分子相互作用发挥致癌作用^[19-21]。例如, CARM1可协助癌基因c-MYC、CUL4A/4B在CRC中发挥促癌作用。CARM1与c-MYC、MYC关联因子X (MYC-associated factor X, Max)、组蛋白乙酰转移酶p300形成CPCM (CARM1-p300-c-Myc-Max)复合物, 该复合物结合在CUL4A/4B启动子区域并诱导其表达, 进而激活CRL4 E3连接酶以降解抑癌蛋白7 (suppressor of tumorigenicity 7, ST7), 从而解除ST7对肿瘤生长的抑制作用, 促进CRC细胞增殖^[19]。核糖体生产因子2 (ribosome production factor 2 homolog, RPF2)在CRC细胞中高表达, 并通过直接上调CARM1的表达激活蛋白激酶B (protein kinase B, AKT)/糖原合酶激酶-3β (glycogen synthase kinase-3beta, GSK-3β)信号通路, 进而诱导上皮-间充质转化(epithelial-mesenchymal transition, EMT)、促进CRC细胞迁移与侵袭^[20]。此外, CARM1与RPF2的相互作用不仅参与调控CRC的恶性进展, 而且参与CRC耐药^[21]。Lu等^[21]发现, RPF2通过调控CARM1-N-myc原癌基因蛋白(N-myc proto-oncogene protein, MYCN)信号通路以上调ATP结合盒B1 (ATP-binding cassette B1, ABCB1)蛋白表达, 促进药物外排, 导致CRC对化疗药物耐药。

在调控肿瘤细胞代谢方面, CARM1通过调节磷酸戊糖途径(pentose phosphate pathway, PPP)中的酶促进癌细胞代谢, 进而促进CRC细胞存活与生长^[22]。CARM1可甲基化核糖-5-磷酸异构酶A (ribose-5-phosphate isomerase A, RPIA)的R42以上调其催化活性, 在葡萄糖饥饿条件下, CARM1与RPIA的结合增强, 诱导R42超甲基化, 从而提升PPP代谢通量; 另外, R42的甲基化一方面可促进NADPH生成以清除ROS、抑制癌细胞凋亡, 另一方面可增加DNA合成, 促进癌细胞的存活与生长^[22]。长链脂肪酸-CoA连接酶4 (long-chain fatty acid-CoA ligase 4, ACSL4)在铁死亡中发挥重要作用^[53], 也是CARM1的底物之一。CARM1通过甲基化ACSL4的R339促进RNF25与ACSL4结合, 进而诱导ACSL4发生泛素化降解, 降低脂质过氧化物积累, 从而拮抗铁死亡, 抑制CARM1可降低其对ACSL4的甲基化, 恢复铁死亡敏感性, 这提示CARM1是基于铁死亡抗肿瘤的候选治疗靶点^[23]。CARM1在CRC细胞中的作用及分子机制如图2所示。

1.4　PRMT5

PRMT5是一种主要的Ⅱ型PRMT家族成员, 主要存在于细胞核中, 可诱导精氨酸单甲基化和对称二甲基化。在信号转导中, PRMT5作为一个重要的表观遗传因子参与染色质重塑、细胞代谢、细胞周期调控和癌症发生等过程^{[54, 55]}。PRMT5的表达水平与CRC患者的生存率呈负相关, 可用于预测CRC患者预后^[30]。PRMT5在结直肠癌细胞中高表达, 可通过多种途径促进CRC的生长与迁移。此外, 相对于KRAS野生型细胞, 在KRAS突变型CRC细胞中, 抑制PRMT5能显著抑制肿瘤细胞增殖, 故PRMT5也可作为KRAS突变型CRC的治疗替代靶标^[56]。

在调节CRC细胞增殖方面, PRMT5可通过调节CRC细胞代谢促进增殖^[24]。Shen等^[24]发现, PRMT5能转录激活乳酸脱氢酶A (lactate dehydrogenase A, LDHA), 增强糖酵解并促进CRC细胞增殖。在CRC中, PRMT5与zeste同源物增强子2 (enhancer of zeste homolog 2, EZH2)相结合, PRMT5催化形成的H4R3me2s和H3R8me2s与EZH2催化的H3K27me3皆沉积在CDKN2B基因核心启动子区, 协同抑制细胞周期关键基因CDKN2B的表达, 降低CDKN2B在CRC中的抑癌作用, 进而推动CRC的进展。PRMT5和EZH2的高表达也与CRC患者的预后不良显著相关^[25]。此外, PRMT5通过激活EGFR/AKT/GSK-3β信号级联来促进CRC细胞增殖^[57]。核因子κB (the nuclear factor-kappa B, NF-κB)信号通路与CRC的发生发展密切相关, 对CRC细胞增殖、凋亡、转移等生物学行为至关重要^[55]。Hartley课题组^{[26, 27]}提出PRMT5可能通过PRMT5/YBX1/NF-κB和PKCι/PRMT5/NF-κB分子路径激活NF-κB, 并参与CRC的恶性增殖, 提示靶向抑制PRMT5是一种潜在的CRC治疗策略。

在促进CRC的EMT和转移方面, PRMT5通过甲基化Smad4的常见突变位点R361, 促进Smad复合物(Smad2/3/4)的形成, 并诱导Smad复合物易位至细胞核, 激活转化生长因子(transforming growth factor-β, TGF-β)信号通路, 从而促进由TGF-β1诱导的EMT和CRC转移^[28]。Zheng等^[29]发现, PRMT5可与ZEB2、TWIST1、NuRD形成一种转录抑制复合物, 该复合物可在E-cadherin启动子上甲基化H4R3、去乙酰化H3K56, 从而在表观遗传学水平上抑制CRC细胞中E-cadherin的转录, 进而诱导CRC的EMT、侵袭和转移。微小染色体维持蛋白7 (minichromosome maintenance proteins 7, MCM7)与CRC细胞增殖、迁移及侵袭相关, 也是PRMT5的结合底物之一。PRMT5与MCM7相结合可能通过调控DNA复制进程协同促进CRC增殖、迁移与侵袭^[30]。此外, PRMT5也可通过激活EGFR/AKT/GSK-3β信号级联促进CRC的EMT^[57]。

在免疫治疗方面, PRMT5可调控肿瘤浸润B细胞的功能并参与调控CRC病理过程。Zhou等^[58]研究证明, B细胞条件敲除PRMT5 (CD19-cre-PRMT5^fl/fl, PRMT5cko)小组的小鼠肿瘤体积相较对照组更小, 肿瘤组织中的浸润T细胞增加, 这是由于PRMT5缺失的B细胞可诱导Ccl22和Il12a的表达, 这些分子可能增强T细胞在肿瘤部位的趋化作用, 并增强抗肿瘤活性。此外, PRMT5可在肠道黏膜防御中发挥重要作用。PRMT5通过其甲基转移酶活依赖性和非依赖性机制调控典型隐窝杯状细胞基因的表达, 进而调节肠道黏液产生、组装和抗微生物应答, 增强肠道黏液防御, 这表明PRMT5可作为黏膜防御的新型调节剂和治疗肠道疾病的潜在治疗靶点^[59]。

1.5　PRMT6

PRMT6是一种Ⅰ型精氨酸甲基转移酶, 主要通过催化H3组蛋白2位上的精氨酸残基发生不对称二甲基化(H3R2me2a)发挥基因沉默的表观遗传调节作用。除组蛋白外, PRMT6还可催化非组蛋白的甲基化, 进而调控各种生物学过程。PRMT6在乳腺癌、肺癌、膀胱癌和前列腺癌等恶性肿瘤中异常上调并影响癌症发展^[60]。研究发现, PRMT6表达水平在CRC组织中异常升高, 其高表达与较高的组织学肿瘤分级、肿瘤大小、淋巴结转移和肿瘤分期有关^[31]。PRMT6可通过抑制细胞周期调节因子(如CDKN2B、CCNG1等)的转录促进CRC发生^[31]。值得注意的是, Chen等^[31]发现, PRMT家族的另一成员PRMT5可与PRMT6作为一个功能单元协同发挥作用。PRMT6催化形成的H3R2me2a与PRMT5催化形成的H4R3me2s和H3R8me2s可沉积在CDKN2B (p15^INK4b)和CCNG1的启动子处, 共同抑制CDKN2B (p15^INK4b)和CCNG1表达, 促进CRC进展。PRMT5抑制剂和PRMT6抑制剂联用能够发挥协同抗结直肠癌效果, 这暗示了同时靶向PRMT5和PRMT6治疗CRC的联合用药策略^[31]。

1.6　PRMT7

PRMT7是目前发现的唯一一个Ⅲ型PRMT, 仅催化底物生成MMA, 且能特异性结合被碱性氨基酸包围的RXR基序。PRMT7主要甲基化甘氨酸和精氨酸。与其他PRMTs不同的是, PRMT7包含两个折叠在一起的串联结构域, 能形成同源二聚体样结构, 但仅N端结构域具有催化活性, C端则没有^[61]。PRMT7的表达水平在肿瘤组织中显著高于癌旁正常组织。PRMT7介导的甲基化常常发生在与剪接体、RNA转运、mRNA监视途径等相关的蛋白质上, 并与癌症的发生与增殖密切相关^[32]。

异常的可变剪接是构成癌症生物标志物的重要来源^[62]。rs61746794-T等位基因可促进PRPF8介导的PRMT7外显子16的剪接, 从而提高亚型PRMT7-V2的水平, 增加CRC风险^[63]。人源PRMT7基因模型经剪接可形成28个转录本, 其中有6个转录本与外显子16的剪接有关, 分别表示为PRMT7-V1、PRMT7-V2、PRMT7-V3、PRMT7-V4、PRMT7-V5和PRMT7-V6, 其中, PRMT7-V2的过表达能显著增强CRC细胞和CRC异种移植肿瘤的生长^[63]。PRMT7-V2通过催化H4R3和H3R2的精氨酸甲基化, 激活致癌信号通路, 如YAP、AKT、KRAS等, 促进CRC发生^[63]。研究发现, 在乳腺癌、结直肠癌和前列腺癌细胞中, PRMT4/5/7皆高表达, 且与剪接因子hnRNPA1的甲基化及异常可变剪接密切相关。PRMT4/5/7调控hnRNPA1的精氨酸甲基化以调节hnRNPA1与前体mRNA的结合, 并产生PRMT4/5/7共同调控的可变剪接事件, 从而驱动CRC细胞生长^[32]。PRMT4/5/7抑制剂可协同抑制癌细胞生长, 这表明三者可能是结直肠癌治疗的潜在靶标^[32]。

2　靶向PRMTs的小分子抑制剂抗结直肠癌研究进展

收起

结直肠癌发病隐匿, 中晚期患者预后差、生存期较短, 对人类健康的威胁是极其严重的。表观遗传学改变是结直肠癌发生和发展过程中的重要分子机制之一。据报道, PRMTs家族蛋白在结直肠癌中广泛高表达, 与结直肠癌的发生、发展及预后密切相关。因此, PRMTs逐渐被认为是治疗结直肠癌的潜在靶标之一, 不少PRMTs抑制剂被研究报道。本文对当前开发中的应用于结直肠癌治疗的PRMTs小分子抑制剂按照PRMTs类型进行了分类总结, 并整理了其他癌症治疗中应用的PRMTs抑制剂, 总结了这些抑制剂的分子结构, 以期为新型PRMTs小分子抑制剂的分子设计提供重要信息。

2.1　Ⅰ型PRMT抑制剂

MS023是一种PRMT1抑制剂, MS023对PRMT1的选择性高于其他PRMT家族成员, MS023中的胺能与PRMT1的Glu155、Met157和Glu164形成氢键, 其他重要的相互作用包括抑制剂中吡咯环的氮与Glu59之间可形成氢键、异丙氧基与His163形成氢键。MS023通过抑制PRMT1减缓CRC细胞增殖、诱导细胞分化^[64]。PRMT1的类肽抑制剂P2通过氯乙脒(chloracetamidine)弹头共价修饰PRMT1的Cys101, 形成硫醚键, 不可逆抑制酶活性。Cys101是PRMT1特有的活性位点残基, 其他PRMT (如PRMT5)缺乏此位点, 故这类弹头设计可特异性靶向PRMT1的Cys101。P2通过激活caspase-3, 诱导癌细胞凋亡, 并上调自噬标志物LC3-Ⅱ, 诱导自噬, 特异性地杀死HCT116细胞, 提示其有可能开发成为一种低毒稳定的抗CRC药物^[65]。在结肠癌动物模型中, 吡罗昔康和美洛昔康有抑制癌细胞生长的作用, 但对PRMTs (主要是PRMT1和PRMT5)的表达影响较弱或无影响^{[66, 67]}。新型昔康类似物在苯并噻嗪环的2位引入了芳基哌嗪基团(arylpiperazine moiety), 取代了经典昔康(如吡罗昔康、美洛昔康)中的甲基或吡啶甲酰基, 噻嗪的高供电子能力可提高化合物的抗炎活性。这类新型昔康类似物能显著抑制PRMT1和PRMT5, 调节CRC细胞代谢重编程, 发挥抗CRC作用。这种新型昔康类似物比吡罗昔康和美洛昔康作用效果更佳, 能更显著地抑制HT-29和HCT116细胞中的PRMT1和PRMT5, 表明该昔康类似物具有开发成一种新型抗结直肠癌药物的潜力^[67]。

SGC2085是CARM1特异性抑制剂, SGC2085引入的甲基可选择性占据CARM1特有的由Phe153、Gln159和Met163形成的疏水口袋, 利用CARM1与PRMT6在此区域的残基差异(如PRMT6在此处对应残基为Cys50、Val56, 不存在该口袋), 降低对PRMT6的结合, 显著提高选择性。SGC2085在蛋白表达水平和酶活性两个方面皆可抑制CARM1以减缓CRC细胞增殖^{[68, 69]}。此外, SGC2085联合放疗可通过阻滞细胞周期、诱导凋亡和自噬、提高线粒体依赖性的ROS、增加DNA损伤, 增强CRC细胞的放疗敏感性, 并协同抑制癌细胞增殖、迁移与侵袭, 这表明SGC2085可成为一种潜在的放疗增敏剂^[69]。EZM2302是CARM1的选择性抑制剂, EZM2302的二甲基异恶唑基团与CARM1的Glu192、Lys470等残基形成范德华力接触, 此外, EZM2302的氯代苯环可与CARM1的Phe152、Tyr261和Phe474形成π-π堆积作用, 2,7-二氮螺[3.5]壬基与Phe474形成了范德华相互作用, 皆可增强结合稳定性。EZM2302通过阻断CARM1介导的ACSL4甲基化和降解, 诱导细胞铁死亡, 使结肠癌细胞对抗PD-1免疫治疗更敏感。有趣的是, 抗PD-1也可增强EZM2302诱导的CRC细胞铁死亡, 两者联合应用可增强免疫治疗和铁死亡, 发挥协同抗肿瘤效果^{[23, 70]}。

2.2　Ⅱ型PRMT抑制剂

Ⅱ型PRMT抑制剂AMI-1是一种对称磺酰脲类化合物, AMI-1对PRMT5的选择性源于其通过结合PRMT5底物结合口袋以降低PRMT5的催化活性^{[7, 71]}, 这也是人类发现的第一个PRMT小分子抑制剂。有研究表明, AMI-1显著降低了由PRMT5介导的癌基因真核细胞翻译起始因子4E (eukaryotic translation initiation factor 4E, eIF4E)、成纤维细胞生长因子受体3 (fibroblast growth factor receptor 3, FGFR3)启动子上H4R3和H3R8的甲基化, 使癌基因表达下调, 发挥抗CRC疗效, 此外, AMI-1可通过上调p53和促凋亡蛋白Bax、下调抗凋亡蛋白Bcl-2, 诱导CRC细胞凋亡, 并在体内、外显著抑制CRC细胞增殖与迁移^[72]。EPZ015666 (GSK3235025)是全球首个研发的口服有活性的PRMT5选择性抑制剂, Phe580的酰胺、Glu444的侧链和Glu345的侧链通过水介导的相互作用与抑制剂结构中的四氢异喹啉(tetrahydroisoquinoline, THIQ)环的叔氮结合, 值得注意的是, 抑制剂结构中THIQ环与Phe327形成独特的π-π相互作用, 显著增强结合亲和力, 实现对PRMT5的高效选择性^[73]。EPZ015666通过抑制KRAS突变型和野生型CRC细胞中的PRMT5以抑制癌细胞生长、停滞细胞周期, 且在KRAS突变型CRC细胞中治疗效果尤佳, 这也给KRAS突变型CRC患者的治疗带来一线希望^[56]。EPZ015866 (GSK3203591)是PRMT5抑制剂, 通过抑制由PRMT5调节的可变剪接来抑制CRC细胞生长^[32]。此外, PRMT5和EZH2在结直肠癌患者中均高表达, 联合应用PRMT5抑制剂EPZ015866和EZH2抑制剂GSK126可激活CDKN2B、在体内外对CRC细胞生长发挥协同抑制作用^[25]。2017年, Prabhu等^[74]应用AlphaLISA高通量筛选技术发现了一种可特异性抑制PRMT5的小分子化合物PR5-LL-CM01, PR5-LL-CM01靶向PRMT5的甲基转移酶活性口袋, 直接与残基Glu444形成氢键, 抑制酶的催化活性。PR5-LL-CM01能降低HT-29细胞中PRMT5介导的NF-κB的激活并抑制结直肠癌细胞增殖, 且有效浓度约为已上市的PRMT5抑制剂EPZ015666的1/10~1/15, 因此PR5-LL-CM01可能在抗肿瘤疗效上具有更大的开发潜力。除上述选择性小分子抑制剂外, 有些药物也发挥抑制PRMTs的作用, 如抗病毒药物利巴韦林。研究表明, 在CRC细胞中, 利巴韦林能抑制PRMT5的表达, 并使PRMT5介导的H3R8me2s显著富集在eIF4E启动子区, 抑制eIF4E的转录, 导致细胞周期停滞在S期, 从而抑制癌细胞增殖与集落形成, 发挥抗CRC作用^[75]。他达拉非也可通过阻断PRMT5来抑制糖酵解, 进而抑制CRC细胞生长。此外, 他达拉非还可以增强5-FU的抗CRC作用^[24]。

2.3　Ⅲ型PRMTs抑制剂

SGC3027是首个被开发出的具有PRMT7选择性的细胞活性化学探针。SGC3027是一种前药, 在体内可转化为活性形式SGC8158, SGC8158的联苯甲胺基团向PRMT7保守的THW环(Arg311-Met315)区域延伸, 占据由Trp282、Phe146、Tyr48、Met296、Arg44和Arg311侧链组成的疏水口袋, 并与Trp282形成边缘到面的π-π堆积作用, 稳定化合物的结合, 此外, SGC8158的核糖部分占据PRMT7的S-腺苷甲硫氨酸(SAM)结合口袋, 这与辅因子SAH (S-腺苷高半胱氨酸)的核糖位置几乎重叠, 表明SGC8158通过与SAM竞争性结合PRMT7活性位点, 以抑制酶活性, SGC8158通过有效阻断PRMT7抑制CRC细胞生长^{[63, 76, 77]}。上述PRMTs小分子抑制剂的作用靶点、结构式、作用机制等研究概况总结见表2。

2.4　应用于其他癌症中的PRMTs小分子抑制剂

GSK3368715是一种I型PRMTs抑制剂, 通过与PRMT的底物结合口袋结合, 非竞争性抑制SAM, 其结构与MS023类似, 吡唑环作为主要药效团, 与PRMT1的底物结合位点相互作用。GSK3368715烷基链上的仲胺与PRMT1的Glu162侧链之间有很强烈的相互作用, 叔胺与His311有相互作用, 重氮唑的仲胺与Glu65之间存在相互作用。GSK3368715在胰腺癌和弥漫性大B细胞淋巴瘤细胞系中与PRMT5抑制剂GSK3203591联合使用时具有显著的抗肿瘤增殖作用^[78]。

DB75是具有双脒基团的PRMT1抑制剂, 其中一个脒基团与Glu144和Glu153相互作用, 它们是催化酶活性的必需残基, 而另一个脒基团与SAM结合口袋周围的Glu129相互作用, 此外, DB75与PRMT1的YFXY基序Tyr35、Phe36和Tyr39以及与Met146、Met155和Thr158通过π-π或疏水相互作用作用稳定其与酶的结合^[79]。相比于DB75, K313通过引入吲哚环和苯胺这一连接链优化了疏水性与刚性, 增强了与PRMT1活性位点的互补性, 这一结构差异使其抑制PRMT1的效力约为DB75的5~10倍; 因为连接链延长, K313的结合模式与DB75不同, K313从SAM结合口袋的腺苷结合区域延伸到了蛋氨酸结合区域^[80]。

LLY-283是一种高效的PRMT5选择性抑制剂。与底物竞争性PRMT5抑制剂EPZ015666和GSK591相比, LLY-283作为辅因子竞争性抑制剂起作用, 可直接结合SAM口袋。LLY-283的腺嘌呤环与Asp419的侧链和Met420的氨基形成氢键, 其核糖部分则分别与Glu392的谷氨酸侧链和Tyr324的侧链也形成氢键, 另外, LLY-283中的苯基通过空间效应调整结合位点(置换PRMT5中Phe327的侧链)。LLY-283的抗肿瘤增殖作用在一系列癌细胞系中得到证实, 包括血液肿瘤(如淋巴瘤、白血病)和实体瘤(乳腺癌、肺癌、黑色素瘤等)^[81]。

SGC707是基于含二氢噻二唑和环己烯环的先导化合物优化而来PRMT3抑制剂。优化后, 苯并噻二唑基团被替换为异喹啉基团, 后者与Thr466形成氢键, 异喹啉如被替换为萘基后则化合物完全失活, 表明异喹啉-Thr466所形成的氢键对化合物活性至关重要。Arg396与脲基形成氢键, Lys392与吡咯烷酰胺可能形成直接或水介导的相互作用^[82]。

TP-064是CARM1有效的、选择性和具有细胞活性的化学探针, 其末端苯基与Pro473和Phe475形成疏水性相互作用, 吡啶基与Phe153有π堆积相互作用, 另外, 二苯醚的氧与Asn266形成氢键, TP-064尾部的甲基氨基乙基与Glu258、Met260、His415形成氢键。TP-064对部分多发性骨髓瘤细胞系(如NCI-H929、RPMI8226)具有强效抑制作用, 其机制是TP-064通过抑制CARM1引起NCI-H929细胞G0/G1期周期阻滞^[83]。MS049是CARM1和PRMT6的双重抑制剂, 其体积较小, 结构仅由哌啶基乙胺部分、中间接头和苯基三部分组成。哌啶基乙胺部分, 末端胺和哌啶基氮之间的原子数在很大程度上影响了化合物的效力。接头部分, 两个原子的接头可提高CARM1和PRMT6的效力, 如有杂原子也会产生极性相互作用, 故MS049的接头以醚形式设计而成^[84]。

MS117是首个靶向PRMT6的高效、不可逆的共价抑制剂。其结构基于PRMT6-MS023的共晶结构设计而成, MS023中苯基的间位从异丙氧基取代替换成丙烯酰胺取代, 后者能与PRMT6活性位点的亲核残基(如Cys50)形成共价键, 导致酶功能不可逆失活^[85]。

3　总结与展望

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结直肠癌患者术后生存期短, 死亡率高, 且多数患者确诊时已处于晚期, 治疗难度大, 若癌症已发生转移, 预后更差。由PRMTs失调引起的表观遗传学改变与CRC的发生、恶化、不良预后高度相关。大量研究表明PRMTs作为一种癌蛋白可通过调节癌症相关基因表达、改变关键信号分子路径、引发可变剪接等机制促进CRC细胞过度增殖、代谢异常、侵袭和转移^{[6, 7]}。但PRMTs也可在CRC中作为肿瘤抑制因子发挥积极治疗作用, 如抑制免疫逃逸, 成为靶向PRMT1抗CRC治疗的不利因素, 这也提示未来开发抗CRC的PRMTs抑制剂类药物应兼顾抑制PRMTs的同时不唤起PRMTs所介导的肿瘤免疫逃逸^[16]。近年来PRMTs在CRC中的具体作用机制及其底物谱相关报道并不广泛, 因此, 本文对PRMTs调控CRC潜在分子机制的总结还存在一定局限性, 对于Ⅰ、Ⅱ和Ⅲ型PRMTs影响CRC病理过程的机制及3类PRMTs之间作用底物的特异性与共性仍需进一步研究。

原癌基因RAS编码的KRAS蛋白与肿瘤的生成、迁移及耐药密切相关^[86]。研究表明, KRAS突变在近45%的CRC患者中皆有发生, 其突变参与CRC的发生、恶化及不良预后^[86]。这使KRAS突变型CRC患者的临床治疗非常不利。有研究指出, 在KRAS突变型CRC细胞中, 抑制高表达的PRMT5表现出了更好的治疗效果, 这表明不依赖于KRAS基因型, 抑制PRMT5可有效治疗CRC, 提示PRMT5可代替突变的KRAS成为该亚型CRC治疗的替代靶标, 这为KRAS突变型CRC患者的治疗提供新方向^[56]。目前, 多种基因突变, 如SMARCA、KRAS等, 给CRC患者的有效治疗增加了难度^{[43, 56]}。基因突变可能引起蛋白质功能位点的构象发生改变, 由于其中某些蛋白通过与PRMTs相互作用影响CRC进展, 因此深刻揭示PRMTs调控CRC的分子机制是亟需解决的科学问题。此外, 以PRMTs为替代靶点进行靶向治疗或PRMTs抑制剂与突变位点抑制剂联用也逐渐成为抗CRC药物研究领域的热点, 可能为开发CRC精准治疗药物提供更多更优的选择^{[14, 43]}。研究可变剪接对阐明CRC发病机制十分重要, 而目前基于PRMTs剪接变异体影响CRC的相关研究十分稀少。2023年, Zhang等^[63]建立了信息丰富的剪接数量性状基因座(splicing quantitative trait loci, sQTLs), 将可变剪接事件与遗传位点联系起来, 从基因层面深入辅助探讨PRMTs剪接变异体在CRC中的作用机制, 这对未来推动在基因水平研究PRMTs及其剪接体与CRC的关系以及发现CRC潜在生物标志物与治疗分子靶标有重要意义。

在针对特定PRMT的底物筛选及抑制剂优化方面, 针对研究较少的PRMT家族成员(如PRMT3、PRMT7), 可结合蛋白质组学技术(如质谱分析)和CRISPR筛选, 系统性鉴定其甲基化底物, 并验证这些底物在CRC增殖、转移及免疫逃逸中的功能, 如PRMT7剪接变异体(如PRMT7-V2)通过调控YAP/AKT信号促进CRC进程的底物及具体机制尚未有完备解释, 仍需深入解析。

通过解析PRMTs的特异性功能位点或PRMTs与抑制剂相结合的复合物结构, 优化关键药效团, 以提高选择性并降低脱靶效应。例如, 未来可针对PRMT1特有的Cys101位点开发共价抑制剂(如肽类抑制剂P2), 可极大增强抑制剂靶向性。针对PRMT5抑制剂GSK025的优化, 首先应维持THIQ苯环的电子特性以保留其独特的阳离子-π相互作用, 同时调整取代基以优化溶解度或代谢稳定性; 其次, 在侧链基团的非关键区域可引入位阻基团(如甲基、卤素), 减少抑制剂与其他酶的疏水口袋结合可能性; 另外, 在远离结合位点的位置引入极性基团(如羟基、胺基), 增强水溶性并降低非特异性结合。运用前药策略或代谢位点封闭(如引入氟原子)策略, 延长半衰期、减少血浆清除率, 可进一步优化ADME性质, 提高药效。

PRMTs与CRC关联紧密, 既可作为CRC诊断标志物、患者预后的预测因子, 也被认为是有较大开发潜力的CRC治疗靶点。但目前靶向PRMTs抗CRC药物开发仍处于起步阶段, 大部分抑制剂还处于临床前研究中。未来还需要进一步探究PRMTs抑制剂在CRC中更精准的治疗作用, 以期开发出更安全、高效的PRMTs抑制剂为CRC患者谋福祉。

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2026年第61卷第1期

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doi: 10.16438/j.0513-4870.2025-0298

接收时间：2025-03-19
首发时间：2026-09-21
出版时间：2026-01-12

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收稿日期：2025-03-19
修回日期：2025-06-17

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天津医科大学药学院, 天津 300070

通讯作者:

孔德新, E-mail: kongdexin@tmu.edu.cn

邱玉玲, E-mail: qiuyuling@tmu.edu.cn

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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PRMTs	Expression	Substrate	Outcome	Relevant pathway	Ref.
PRMT1	High	hnRNPK	Cancer proliferation, migration and invasion	Methylate hnRNPK and regulate gene transcription	[12]
SMARCA4	Cancer proliferation, migration and poor prognosis	Activate EGFR signaling pathway	[13]
NONO	Cancer proliferation, migration and invasion	Methylate NONO	[14]
PGK1	Cancer proliferation	Enhance glycolysis	[15]
RIP3	Prevent immune escape	Block necroptosis	[16]
PRMT3	High	HIF1α	Tumorigenesis	Activate HIF1α/VEGFA signaling pathway	[17]
c-MYC	Cancer proliferation, migration and invasion	Inhibit the ubiquitination of c-MYC and stabilize c-MYC	[18]
PRMT4	High	p300-c-Myc-Max	Cancer proliferation	Degrade ST7	[19]
RPF2	Cancer invasion, metastasis and drug resistance	Induce EMT by activating AKT/GSK-3β signaling pathway; up-regulate expression of ABCB1 by regulating CARM1-MYCN pathway	[20, 21]
RPIA	Tumor growth	Enhance PPP	[22]
ACSL4	Tumor growth	Induce ubiquitylation of ACSL4 and inhibit ferroptosis	[23]
PRMT5	High	LDHA	Cancer proliferation	Enhance glycolysis	[24]
EZH2	Cancer progression and poor prognosis	Repress expression of CDKN2B	[25]
YBX1, PKCι	Cancer proliferation	Activate NF-κB signaling pathway	[26, 27]
Smad4	Cancer metastasis	Activate TGF-β signaling pathway and induce EMT	[28]
ZEB2-TWIST1-NuRD	Cancer metastasis	Suppress transcription of E-cadherin and induce EMT	[29]
MCM7	Cancer proliferation, migration and invasion	Bind with MCM7 to enhance MCM7 oncogenic functions	[30]
PRMT6	High	CDKN2B, CCNG1	Tumorigenesis and cancer progression	Repress transcription of cell cycle regulators	[31]
PRMT7	High	hnRNPA1	Tumor growth	Methylate hnRNPA1	[32]

PRMTs

Expression

Substrate

Outcome

Relevant pathway

Ref.

PRMT1

High

hnRNPK

Cancer proliferation, migration and invasion

Methylate hnRNPK and regulate gene transcription

[12]

SMARCA4

Cancer proliferation, migration and poor prognosis

Activate EGFR signaling pathway

[13]

NONO

Cancer proliferation, migration and invasion

Methylate NONO

[14]

PGK1

Cancer proliferation

Enhance glycolysis

[15]

RIP3

Prevent immune escape

Block necroptosis

[16]

PRMT3

High

HIF1α

Tumorigenesis

Activate HIF1α/VEGFA signaling pathway

[17]

c-MYC

Cancer proliferation, migration and invasion

Inhibit the ubiquitination of c-MYC and stabilize c-MYC

[18]

PRMT4

High

p300-c-Myc-Max

Cancer proliferation

Degrade ST7

[19]

RPF2

Cancer invasion, metastasis and drug resistance

Induce EMT by activating AKT/GSK-3β signaling pathway; up-regulate expression of ABCB1 by regulating CARM1-MYCN pathway

[20, 21]

RPIA

Tumor growth

Enhance PPP

[22]

ACSL4

Tumor growth

Induce ubiquitylation of ACSL4 and inhibit ferroptosis

[23]

PRMT5

High

LDHA

Cancer proliferation

Enhance glycolysis

[24]

EZH2

Cancer progression and poor prognosis

Repress expression of CDKN2B

[25]

YBX1, PKCι

Cancer proliferation

Activate NF-κB signaling pathway

[26, 27]

Smad4

Cancer metastasis

Activate TGF-β signaling pathway and induce EMT

[28]

ZEB2-TWIST1-NuRD

Cancer metastasis

Suppress transcription of E-cadherin and induce EMT

[29]

MCM7

Cancer proliferation, migration and invasion

Bind with MCM7 to enhance MCM7 oncogenic functions

[30]

PRMT6

High

CDKN2B, CCNG1

Tumorigenesis and cancer progression

Repress transcription of cell cycle regulators

[31]

PRMT7

High

hnRNPA1

Tumor growth

Methylate hnRNPA1

[32]

Drug	Target	Mechanism	Ref.
MS023	PRMT1	Induce cancer differentiation and inhibit proliferation	[64]
A peptide inhibitor	PRMT1	Induce apoptosis and autophagy	[65]
Oxicam analogues	PRMT1/PRMT5	Metabolic reprogramming	[67]
SGC2085	CARM1	Inhibit cancer proliferation	[68, 69]
EZM2302	CARM1	Induce ferroptosis and sensitize CRC cells to anti-PD-1 immunotherapy	[23, 70]
AMI-1	PRMT5	Down-regulate expression of eIF4E and FGFR3; promote apoptosis	[72]
GSK3235025	PRMT5	Inhibit tumor growth; cell cycle arrest	[56, 73]
GSK3203591	PRMT5	Suppress alternative splicing regulated by PRMT5	[32]
PR5-LL-CM01	PRMT5	Inhibit NF-κB pathway and tumor growth	[74]
Ribavirin	PRMT5	Reduce expression of eIF4E; cell cycle arrest	[75]
Tadalafil	PRMT5	Inhibit glycolysis; sensitizes CRC cells to 5-FU	[24]
SGC3027	PRMT7	Inhibit tumor growth	[63, 76, 77]

Drug

Target

Chemical structure

Mechanism

Ref.

MS023

PRMT1

Induce cancer differentiation and inhibit proliferation

[64]

A peptide inhibitor

PRMT1

Induce apoptosis and autophagy