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丝氨酸羟甲基转移酶抑制剂在肿瘤治疗中的研究进展

陈宜利, 王培森, 陈昱灵, 曾园园

陈宜利,王培森,陈昱灵,等. 丝氨酸羟甲基转移酶抑制剂在肿瘤治疗中的研究进展[J]. 中国临床医学, 2025, 32(1): 125-134. DOI: 10.12025/j.issn.1008-6358.2025.20241030
引用本文: 陈宜利,王培森,陈昱灵,等. 丝氨酸羟甲基转移酶抑制剂在肿瘤治疗中的研究进展[J]. 中国临床医学, 2025, 32(1): 125-134. DOI: 10.12025/j.issn.1008-6358.2025.20241030
CHEN Y L, WANG P S, CHEN Y L, et al. Research progress of serine hydroxymethyltransferase inhibitors in tumor treatment[J]. Chin J Clin Med, 2025, 32(1): 125-134. DOI: 10.12025/j.issn.1008-6358.2025.20241030
Citation: CHEN Y L, WANG P S, CHEN Y L, et al. Research progress of serine hydroxymethyltransferase inhibitors in tumor treatment[J]. Chin J Clin Med, 2025, 32(1): 125-134. DOI: 10.12025/j.issn.1008-6358.2025.20241030

丝氨酸羟甲基转移酶抑制剂在肿瘤治疗中的研究进展

基金项目: 国家自然科学基金(82272648), 江苏省高等学校自然科学研究项目(22KJB320006).
详细信息
    作者简介:

    陈宜利,硕士生. E-mail: 2785237050@qq.com

    通讯作者:

    曾园园: Tel: 0512-65223637, E-mail: zengyuanyuan0921@163.com

  • 中图分类号: R 730.5

Research progress of serine hydroxymethyltransferase inhibitors in tumor treatment

Funds: Supported by National Natural Science Foundation of China (82272648), The Natural Science Foundation of the Jiangsu Higher Education Institutions of China (22KJB320006).
  • 摘要:

    肿瘤是细胞长期、无限增殖的结果。肿瘤细胞通过调整各种代谢通量,以满足增加的生物能量和生物合成需求。丝氨酸是人体8种非必需氨基酸之一,在多种生理活动中发挥重要作用,为细胞增殖提供一碳单位、甘氨酸等。丝氨酸羟甲基转移酶(serine hydroxymethyltransferase, SHMT)是催化丝氨酸和甘氨酸转化的关键酶,在多种肿瘤中高表达,是抗肿瘤药物的潜在靶点。本文综述了SHMT作为肿瘤治疗新靶点的潜力及其抑制剂在肿瘤临床前研究中的进展,为新型肿瘤靶向药物研发提供参考。

    Abstract:

    Tumor is the result of long-term and unlimited proliferation of cells. Tumor cells adjust various metabolic fluxes to meet increased bioenergy and biosynthetic requirements. Serine is one of the eight non-essential amino acids in the human body. It plays an important role in a variety of physiological activities and can provide one carbon unit, glycine, etc. for cell proliferation. Serine hydroxymethyltransferase (SHMT) is a key enzyme that catalyzes the conversion of glycine and serine. It is highly expressed in a variety of tumors and is a potential target for anti-tumor drugs. This article focuses on the potential of SHMT as a new target for cancer treatment and the preliminary application of its inhibitors in preclinical studies of tumors, providing reference for the development of new targeted drugs for tumors.

  • 肿瘤是全球范围内的重大公共卫生问题。恶性肿瘤细胞具有无限增殖的特性。受肿瘤细胞自身的DNA突变累积、表观遗传学改变和肿瘤微环境(tumor microenvironment, TME)中细胞因子的联合作用,肿瘤细胞出现代谢重编程,以满足其生长与增殖的需求。研究[1-2]表明,肿瘤细胞的快速增殖、高葡萄糖摄入和有氧糖酵解(Warburg效应)与叶酸依赖的一碳单位代谢密切相关。不同于正常细胞,即使在有氧条件下,肿瘤细胞也更依赖于糖酵解代谢以产生三磷酸腺苷(adenosine triphosphate, ATP),即有氧糖酵解。尽管有氧糖酵解产生ATP的效率较低,但代谢过程中产生的中间产物,包括一碳骨架等,可以促进氨基酸和核苷酸合成,为细胞无限增殖提供原料[3-4]

    代谢重编程是肿瘤细胞的重要特征和标志,靶向癌症特异性代谢途径是一种有前景的治疗策略[5]。目前的研究[6]已确定肿瘤细胞具有6个代谢标志,包括葡萄糖和氨基酸摄取失调,利用糖酵解或三羧酸(tricarboxylic acid, TCA)循环中间产物进行生物合成和还原型烟酰胺腺嘌呤二核苷酸磷酸(reduced nicotinamide adenine dinucleotide phosphate, NADPH)生产,氮需求量增加,代谢物驱动基因调控的改变,与TME进行代谢性互作和利用最佳生存模式获取营养物质。除此以外,肿瘤细胞内脂肪酸、一碳单位、天冬氨酸以及丝氨酸等代谢通路也发生改变,以满足肿瘤细胞对生物合成、能量供应和氧化还原平衡的需求。其中,一碳代谢有助于生物大分子(蛋白质、核苷酸等)和功能代谢物[ATP、谷胱甘肽(glutathione, GSH)、还原型烟酰胺腺嘌呤二核苷酸(reduced nicotinamide adenine dinucleotide, NADH)等]的生物合成以维持癌症进展[7]。肿瘤细胞中的一碳单位主要来源于丝氨酸。研究[5-8]表明,抑制肿瘤细胞内参与丝氨酸代谢的酶可显著抑制肿瘤生长。

    丝氨酸属于非必需氨基酸,是哺乳动物维持蛋白质、核苷酸和脂质生物合成,促进细胞生长所需的重要营养物质[9-11]。机体可通过3种途径获取丝氨酸:(1)自身合成途径。由磷酸甘油酸脱氢酶(phosphoglycerate dehydrogenase, PHGDH)、磷酸丝氨酸氨基转移酶1(phosphoserine aminotransferase 1, PSAT1)和磷酸丝氨酸磷酸酶(phosphoserine phosphatase, PSPH)催化合成[11]。(2)氨基转换作用。当细胞无法通过自身合成满足对丝氨酸的需求时,丝氨酸羟甲基转移酶(serine hydro-xymethyltransferase, SHMT)1/2可催化甘氨酸转换为丝氨酸[12]图1)。(3)直接从外界摄取。

    图  1  SHMT调控甘氨酸和丝氨酸相互转换
    Figure  1.  SHMT catalyzes the reversible conversion of glycine to serine
    THF: tetrahydrofolate; SHMT: serine hydroxymethyltransferase.

    丝氨酸参与调控细胞周期,诱导细胞周期检查点激酶2和细胞周期蛋白D1表达[13]。丝氨酸合成过程中产生的NADH不仅参与氧化磷酸化,还作为辅助因子参与脯氨酸和脂质合成。此外,丝氨酸在SHMT2的催化下转变成甘氨酸,参与还原型谷胱甘肽(glutathione, GSH)合成,在维持细胞内氧化还原平衡中发挥重要作用[14]图2)。

    图  2  SHMT参与丝氨酸-甘氨酸-一碳代谢途径
    Figure  2.  SHMT participates in the serine-glycine-one-carbon metabolism
    THF: tetrahydrofolate; TYMS: thymidylate synthase; MTHFR: 5,10-methylenetetrahydrofolate reductase; SHMT: serine hydroxymethyltransferase; MTHFD1: methylenetetrahydrofolate dehydrogenase 1; NADPH: reduced nicotinamide adenine dinucleotide phosphate; NADH: reduced nicotinamide adenine dinucleotide; ALDH1L1: aldehyde dehydrogenase 1 family member L1; GSH: glutathione; GSSG: oxidized glutathione; ROS: reactive oxygen species.

    越来越多的证据[15-18]表明,丝氨酸是肿瘤细胞生长、增殖和浸润的关键代谢产物。肿瘤细胞高度依赖于外源丝氨酸的摄入以维持自身快速增殖[19-22]。研究[23]表明,丝氨酸代谢异常激活导致细胞核苷酸、蛋白质和脂质合成异常,影响线粒体代谢功能,改变表观遗传修饰水平。此外,丝氨酸还可作为碳源参与肿瘤细胞一碳代谢[24]。上述生物活动共同驱动肿瘤细胞的恶性转化、无限增殖、转移、免疫抑制和耐药。多项研究[14, 24-26]已证实,丝氨酸耗竭可以显著抑制肿瘤进展。无丝氨酸饮食可以明显延缓小鼠体内淋巴瘤和肠道肿瘤的生长速度,提高小鼠存活率[25-26]。通过饮食限制丝氨酸摄入或耗竭丝氨酸代谢关键酶PHGDH可引起细胞内脱氧鞘脂积累[27],延缓肿瘤生长,延长肿瘤患者的生存期。丝氨酸含量降低可抑制细胞内抗氧化反应、核苷酸合成和TCA循环,增加细胞对放射治疗的敏感性,提升肿瘤患者的治疗效果[28]。随着对丝氨酸代谢调控机制的深入探索,靶向抑制其代谢或可成为肿瘤治疗领域新的突破口。

    SHMT是一种磷酸吡哆醛依赖型酶,参与氧化还原平衡、核苷酸合成及代谢重编程等生物过程。SHMT包括SHMT1和SHMT2两种亚型,其酶活性相同,分别在细胞质和线粒体中催化丝氨酸和甘氨酸间的转换作用。

    SHMT2和SHMT1属于同工酶,两者氨基酸序列一致性约66%[29]。SHMT1在细胞质中发挥作用,主要功能是合成脱氧胸腺嘧啶核苷酸(dTMP)和维生素B6。dTMP可以防止脱氧尿嘧啶核苷酸(dUMP)整合到双链DNA上,对DNA的结构稳定性至关重要[30-31]。SHMT2主要在线粒体中发挥催化作用,将丝氨酸转化为甘氨酸和亚甲基四氢叶酸(CH2-THF)。甘氨酸进入谷胱甘肽和嘌呤代谢通路,而CH2-THF提供一碳单位参与嘌呤和胸腺嘧啶合成,并产生NAPDH,维持细胞内氧化还原平衡[9-32]。因此,SHMT2的活性直接影响氨基酸代谢通路的运转,进而影响细胞生长和分裂。此外,研究[33]发现,敲低SHMT2会导致线粒体呼吸链相关复合物(如复合物Ⅰ和Ⅳ)蛋白表达下调,提示SHMT2不仅在氨基酸代谢中发挥作用,也可以影响线粒体呼吸链。

    SHMT通过不同机制参与肿瘤发生发展、不良预后和耐药,是肿瘤细胞生存的必需因素[31-34]。SHMT2已被证实在多种癌症中高表达,如胶质瘤[31]、结直肠癌[35]、乳腺癌[36]和胰腺癌[37]。SHMT可以通过影响细胞内氧化应激稳态,调控肿瘤细胞对抗外部压力的能力[38]。研究[29]发现,降低SHMT1表达对肝癌和卵巢癌细胞的生长和迁移均存在抑制作用;敲除神经母细胞瘤细胞内SHMT2会导致线粒体功能失调,细胞内活性氧(reactive oxygen species, ROS)上升,诱导肿瘤细胞死亡[39]。上述研究结果均证实,SHMT可作为肿瘤治疗的潜在分子靶点[40]。研发SHMT小分子抑制剂可能对癌症治疗,改善患者预后具有积极作用。

    另有研究[41]发现,采用CRISPR-Cas9基因编辑技术敲除肿瘤细胞SHMT2基因后,细胞可继续存活且仍保有成瘤性,提示细胞内存在代偿机制,即细胞在敲除SHMT2基因后,可依赖SHMT1进行逆反应以维持细胞生理活性。然而,SHMT1的代偿反应只能部分恢复细胞质的一碳单位池,无法满足细胞对甘氨酸的需求,导致SHMT2敲除细胞出现营养缺陷。因此,考虑到血清中丝氨酸和甘氨酸丰富,靶向SHMT2治疗必须与SHMT1抑制相结合。Ducker等[42]发现SHMT1和SHMT2双重敲除的肿瘤细胞丧失成瘤性,证实了SHMT1/2双重靶向抑制剂在肿瘤治疗中的优良前景。

    尽管SHMT在癌症治疗中的作用备受关注,但目前仍没有SHMT靶向抑制剂获批用于临床或处于临床试验中[43]。NSC 127755为首个SHMT不可逆抑制剂,但因其不良反应临床应用受限[44]

    叶酸类似物AGF347对SHMT1和SHMT2均有抑制作用,在多种癌症中表现出抗肿瘤活性[45]。甲酰四氢叶酸是SHMT1的靶向抑制剂[46],但因其在体内易转化为其他叶酸类似物而未能用于临床。SHIN1是一种新型的叶酸竞争性SHMT1/2抑制剂,具有良好的细胞渗透性,可以抑制多种肿瘤细胞增殖[47],但因其药物代谢动力学(pharmacokinetics, PK)参数欠佳,未能开展临床试验。因此,科学家进一步改进SHIN1的化学结构,获得了具有良好PK性质的SHIN2[48]。研究[49]表明,在T细胞急性淋巴细胞白血病(T-cell acute lymphoblastic leukemia, T-ALL)细胞中,SHIN2对一碳代谢有显著抑制作用;在淋巴瘤细胞中,SHIN2显示出对SHMT有效且特异性的靶向抑制活性。

    叶酸代谢酶抑制剂,如洛美曲索、培美曲塞等,也展现出抗肿瘤活性[50]。分子对接试验[44]结果显示,该类药物对SHMT存在一定的抑制作用,且对SHMT1的敏感性高于SHMT2。此外,Geeraerts等[51]在2021年发现,抗抑郁药舍曲林也可以抑制SHMT1/2,抑制各种依赖丝氨酸/甘氨酸合成的肿瘤进展。

    SHMT1在肺癌中高表达,其多态性与肺癌发生风险相关。在肺癌细胞中特异性敲低SHMT1表达,引起DNA复制过程中UMP过量积累,导致细胞周期停滞,诱发细胞凋亡[50]。研究[52]表明,吡喃吡唑类化合物2.12[(4R)-6-氨基-4-乙基-4-(3,5-二氯苯)-1H-吡喃-(2,3-C)吡唑-5-腈]可以优先抑制SHMT1,诱导肺癌细胞凋亡。化合物2.12的抑制能力取决于与SHMT1相结合的氨基酸底物结构。化合物2.12可以与丝氨酸形成氢键,但不能与甘氨酸形成氢键。因此,其与SHMT-丝氨酸二元复合物的亲和力是SHMT-甘氨酸的50倍。补充丝氨酸可提高化合物2.12对SHMT的抑制效能。

    SHMT2促进细胞生长,与肺癌细胞的恶性程度相关[53]。韩天宇教授等[5]经化合物库筛选,发现SHIN1是最有效的SHMT抑制剂之一。SHIN1主要抑制SHMT2,可显著抑制肺腺癌类器官生长。SHIN1可以促进NEDD4样E3泛素连接酶(NEDD4L)与细胞周期依赖性激酶1(cyclin-dependent kinases 1, CDK1)相互作用,加速CDK1降解,使细胞周期停滞在G2/M期,从而显著抑制肺癌细胞增殖。其肿瘤抑制作用存在明显剂量依赖性[49]。另外,SHIN1可导致细胞线粒体膜电位去极化、线粒体氧化应激、代谢损伤,细胞内ATP水平下降,是诱导肺癌细胞铁死亡的候选药物之一[54]

    结肠癌组织中SHMT2蛋白表达明显升高,与结肠癌患者的不良预后密切相关。在结肠癌细胞(HCT116)中敲除SHMT2基因后,SHIN1的半数抑制浓度(inhibitory concentration 50, IC50)显著降低;仅敲除SHMT1后,SHIN1的IC50无明显变化,提示SHIN1主要靶向SHMT2,从而发挥结肠癌细胞抑制作用[42]。SHIN1可下调HCT116中自噬衔接蛋白SQSTM1的表达,破坏细胞稳态,逆转SHMT2过表达对细胞的促增殖作用[55]

    TCGA数据库数据分析[56]显示,SHMT表达升高与胰腺癌患者生存不良相关。使用SHIN1可显著抑制胰腺癌细胞(PaTu 8988t)增殖。PaTu 8988t细胞系存在线粒体一碳代谢的遗传性缺陷,依赖SHMT1将甘氨酸转化为丝氨酸。然而,研究[42]发现,添加甲酸盐却增强了SHIN1对PaTu 8988t细胞的生长抑制作用,提示SHIN1的胰腺癌细胞毒性不是由于一碳单位耗竭,而是甲酸积蓄导致SHMT1激活,催化甘氨酸转化为丝氨酸,加剧了细胞内甘氨酸缺乏,诱导细胞免疫原性死亡。因此,添加甲酸盐或耗竭甘氨酸可能成为一种有效的肿瘤治疗策略。

    此外,叶酸类似物AGF347也可靶向线粒体中的SHMT2,在胰腺癌细胞系(MIA PaCa-Ⅱ)侵袭性肿瘤模型中表现出显著的抗肿瘤活性。实验[45]结果显示,AGF347可破坏肿瘤细胞内线粒体的氧化还原平衡,使肿瘤负荷明显降低,生长速度减缓。AGF347的耐受性良好,暂未发现严重的不良反应,是一种潜在的抗肿瘤化合物。

    乳腺癌细胞高度依赖丝氨酸与甘氨酸合成。浸润性乳腺癌组织中SHMT2表达明显升高,其表达水平与乳腺癌分级正相关。有研究[57-58]发现SHMT2可作为乳腺癌的独立预后因素。敲低SHMT2可通过降低人类造血细胞特异性蛋白1相关蛋白X-1(human HCLS1-associated protein X-1, HAX1)的表达水平,降低乳腺癌细胞系(MCF-7)的侵袭和迁移能力,表明SHMT2在乳腺癌中具有促癌作用。SHIN1可逆转SHMT2过表达的MCF-7细胞的强迁移能力[59],为SHMT抑制剂开发提供了细胞学证据。

    舍曲林是一种选择性血清素再摄取抑制剂(selective serotonin reuptake inhibitors, SSRIs)类抗抑郁药,近来有研究[51]证实其具有SHMT抑制作用。舍曲林通过抑制SHMT1/2活性以及甘氨酸摄取,降低丝氨酸从头合成和净摄取,以剂量依赖性方式抑制丝氨酸合成依赖性乳腺癌、ALL以及非小细胞肺癌(non-small cell lung cancer, NSCLC)细胞的增殖能力。然而,其在肿瘤治疗中的安全性及相关剂量设置仍有待开展临床试验进一步评估。

    SHMT2在膀胱癌组织中高表达,与患者的不良预后相关。体外实验[60]证实,SHMT2表达水平会影响膀胱癌细胞的生长、迁移和凋亡等行为,是潜在的致癌因子。SHMT2通过维持氧化还原平衡以促进肿瘤细胞增殖。SHIN1可抑制SHMT2,降低细胞内NAD+/NADH、NADP+/NADPH和GSH/GSSG比值,促进细胞内ROS蓄积,导致线粒体膜电位去极化、细胞色素C释放、Bcl-2家族蛋白易位和caspase 3激活,触发细胞凋亡机制,从而延缓细胞周期进程,抑制膀胱癌细胞增殖[61]

    与正常血液细胞相比,人T-ALL细胞系中的SHMT2表达升高。研究[47]证实,SHIN2在人T-ALL细胞系中通过抑制SHMT,引起细胞内甘氨酸耗竭,阻断细胞周期,抑制细胞增殖。此外,SHIN2在跨膜受体蛋白(NOTCH1)诱导的小鼠T-ALL模型和患者来源T-ALL的异种移植模型中均表现出抗肿瘤作用。SHIN2的体内外研究[47]均展现出与甲氨蝶呤良好的协同活性,且甲氨蝶呤耐药患者对SHIN2的敏感性增加。提示SHIN2可与甲氨蝶呤联合作为甲氨蝶呤不耐受或耐药患者的替代药物。

    综上所述,SHMT靶向抑制剂有望成为抗肿瘤治疗的又一个里程碑。其主要通过以下机制发挥抗肿瘤作用:(1)扰乱DNA复制过程,阻滞细胞周期;(2)影响蛋白质翻译后修饰过程,导致蛋白质加速降解或异常积累;(3)破坏线粒体稳态,导致细胞内氧化还原失衡;(4)损伤细胞一碳代谢过程,导致细胞营养缺乏和能量供应不足。

    目前,肿瘤单靶向治疗大多具有耐药性和剂量依赖性毒性,限制了其临床应用。而多靶点药物与联合治疗可以提高肿瘤特异性,降低耐药性和不良反应,增强治疗效果,为克服经典的治疗抵抗提供了解决方案[51]。SHMT2虽是多种癌症的潜在治疗靶点,但特异性靶向SHMT2的治疗策略仍充满挑战。例如,靶向抑制SHMT2会发生代偿反应,促进SHMT1将丝氨酸转化为甘氨酸,限制SHMT2抑制剂的治疗效果[37]。因此,SHMT抑制剂的联合用药可能是其治疗的主要方式。

    KRAS和LKB1双突变型NSCLC(KL-NSCLC)对大多数疗法耐受,患者预后差。近期研究[62]发现,KL-NSCLC细胞通过激活SHMT2增强一碳单位生成,维持细胞内氧化还原平衡,该过程依赖NAPDH的产生。SHIN1和SHIN2处理诱导KL-NSCLC细胞氧化应激,导致细胞凋亡。同时抑制SHMT2和催化NADPH生成的3种关键酶[葡萄糖-6-磷酸脱氢酶(glucose-6-phosphate dehydrogenase, G-6-PD)、苹果酸酶1(malic enzyme 1, ME1)和异柠檬酸脱氢酶(isocitrate dehydrogenase, IDH1)]可产生协同效应,进一步抑制KL-NSCLC细胞的增殖能力并增加细胞内NADP+/NADPH比值。此外,联合应用SHIN2和紫杉醇(NSCLC一线治疗药物)可以发挥抑制增殖和促进凋亡的作用,显著提升KL-NSCLC的体内治疗效果。与SHIN2单独用药相比,紫杉醇和SHIN2联合用药可以显著提高SHIN2的血药浓度,提示紫杉醇与SHIN2间具有典型的药物相互作用。紫杉醇通过抑制肝脏中药物代谢酶以减缓SHIN2清除,这可能是两种药物协同作用的原因[63]

    研究[64]表明,SHMT特异性抑制剂SHIN2在较高剂量(200 mg/kg,2次/d,连用11 d)时显示出对T-ALL异种移植的有效体内抑制作用,其疗效与标准治疗药物甲氨蝶呤相当。2022年,Wilke等[65]通过体内和体外研究,证实SHIN2可以与甲氨蝶呤发挥协同作用,降低伯基特淋巴瘤细胞内甘氨酸和甲酸盐水平,触发致癌转录因子TCF3自噬降解,导致B细胞受体信号转导阻滞,诱导伯基特淋巴瘤细胞凋亡。

    乳腺癌细胞发生线粒体功能障碍后,一碳代谢失衡,使得细胞更加依赖丝氨酸/甘氨酸合成以获得生长优势[66]。因此,靶向丝氨酸/甘氨酸合成和线粒体代谢可以协同抑制乳腺癌细胞活性。舍曲林作为SHMT抑制剂单独处理乳腺癌细胞,可以使细胞增殖率降低20%。舍曲林与蒿甲醚(线粒体抑制剂,抑制TCA循环活性)联合应用后,细胞增殖率降低约40%。与单一疗法相比,舍曲林-蒿甲醚联合疗法对乳腺癌异种移植瘤的抑制作用更强。其中,蒿甲醚增强了舍曲林促进G1/S期停滞的作用,证实了线粒体抑制剂与舍曲林联合应用的临床价值[51]。此外,舍曲林联合放射治疗也显著抑制了肿瘤进展,在NSCLC细胞的克隆形成能力和自我更新能力方面均表现出很强的协同抗癌作用[67]

    特异性阻断肿瘤细胞代谢的关键酶SHMT有望切断肿瘤细胞的“燃料供应”,抑制肿瘤扩散。但由于目前研发的抑制剂具有强细胞毒性[44]、非特异性、清除率快[48]或易转化为其他叶酸衍生物[46]等缺陷,目前仍没有特异性靶向SHMT的抑制剂进入临床试验。

    设计SHMT抑制剂,需要掌握SHMT的晶体结构和酶促反应机制。首先,利用中子和X射线等先进技术提供SHMT的原子层面信息,包括每个原子、化学键和电荷的位置等,以确保高亲和力和选择性,提高成药性。其次,可利用高通量同位素反应堆和散裂中子源等先进设施,深入探究SHMT在不同代谢反应中的作用,以及其与各种抑制剂的相互作用机制,明确SHMT抑制剂的吸收、分布、代谢和排泄特性,以提高生物利用度、疗效和安全性。

    此外,分子探针技术可以有效监测酶活性改变。未来可以通过开发特异性分子探针实现对SHMT抑制剂的高通量筛选。然而,由于SHMT催化细胞中必不可少的丝氨酸-甘氨酸转化过程,导致能够进入SHMT活性部位的底物非常有限,阻碍分子探针的开发。研究者们可以通过SHMT催化的其他反应来设计出可响应的分子探针,例如SHMT与β-羟基取代的芳香族氨基酸反应,可催化非四氢叶酸依赖性逆醛醇反应等。对于最终筛选出的SHMT抑制剂,均需要进行充分的临床前研究和临床试验,以评估其药物毒性和分子特异性。

    SHMT是肿瘤和正常组织之间具有显著差异化表达的代谢酶之一,催化丝氨酸代谢,提供核苷酸、氨基酸等营养物质以满足肿瘤细胞的增殖需求,促进肿瘤发生发展。此外,丝氨酸代谢与表观遗传学和线粒体氧化还原状态之间存在关联。探究SHMT代谢功能有助于肿瘤治疗新靶点和特异性途径的开发。

    本文总结了丝氨酸代谢关键酶SHMT的作用,探讨了现有SHMT抑制剂在多种肿瘤中的应用及其联合治疗潜力,并展望了新一代SHMT抑制剂的研发前景(图3)。现有SHMT抑制剂对肿瘤细胞和正常细胞的无差异攻击严重限制了其临床应用,因此,提高药物的选择性和灵敏度是SHMT抑制剂研发的未来方向。目前的肿瘤药物研发仍存在诸多挑战,创新药物分子和疾病靶点的缺失是亟待解决的问题。SHMT抑制剂是近年来发现的肿瘤治疗新方法。相信在不久的将来,SHMT抑制剂也将克服PK性质不佳、靶向性弱等问题,为肿瘤治疗开辟新路径。

    图  3  SHMT抑制剂的抗肿瘤潜力
    Figure  3.  Antitumor potential of SHMT inhibitors
    A: The classification and function of SHMT; B: SHMT inhibitors; C: The anti-tumor mechanism of SHMT inhibitors; D: Combined application of SHMT inhibitors. THF: tetrahydrofolate; SHMT: serine hydroxymethyltransferase.

    伦理声明 无。

    利益冲突 所有作者声明不存在利益冲突。

    作者贡献 陈宜利:查阅文献,绘制插图,撰写论文;王培森、陈昱灵:调研文献,修改论文;曾园园:整体构思、框架搭建,指导及修改论文。

  • 图  1   SHMT调控甘氨酸和丝氨酸相互转换

    Figure  1.   SHMT catalyzes the reversible conversion of glycine to serine

    THF: tetrahydrofolate; SHMT: serine hydroxymethyltransferase.

    图  2   SHMT参与丝氨酸-甘氨酸-一碳代谢途径

    Figure  2.   SHMT participates in the serine-glycine-one-carbon metabolism

    THF: tetrahydrofolate; TYMS: thymidylate synthase; MTHFR: 5,10-methylenetetrahydrofolate reductase; SHMT: serine hydroxymethyltransferase; MTHFD1: methylenetetrahydrofolate dehydrogenase 1; NADPH: reduced nicotinamide adenine dinucleotide phosphate; NADH: reduced nicotinamide adenine dinucleotide; ALDH1L1: aldehyde dehydrogenase 1 family member L1; GSH: glutathione; GSSG: oxidized glutathione; ROS: reactive oxygen species.

    图  3   SHMT抑制剂的抗肿瘤潜力

    Figure  3.   Antitumor potential of SHMT inhibitors

    A: The classification and function of SHMT; B: SHMT inhibitors; C: The anti-tumor mechanism of SHMT inhibitors; D: Combined application of SHMT inhibitors. THF: tetrahydrofolate; SHMT: serine hydroxymethyltransferase.

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出版历程
  • 收稿日期:  2024-09-21
  • 录用日期:  2024-12-19
  • 网络出版日期:  2024-12-29
  • 刊出日期:  2025-02-24

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