摘要
随着肿瘤免疫疗法(tumor immunotherapy)的兴起,靶向免疫系统的小分子调节剂已成为研究热点,而免疫激酶作为一类研究较深入发展较成熟的靶点,受到越来越多的关注。丝裂原活化蛋白激酶(MAPK)相互作用激酶(MNKs)位于ERK和p38 MAPK信号通路的交汇点,可以在保守的丝氨酸209处特异性磷酸化真核翻译起始因子4E(eIF4E)并调节mRNA的翻译。MNKs信号通路在先天性和适应性免疫系统中起着重要作用,MNKs抑制剂在治疗肿瘤及免疫相关疾病的研究也越来越深入。本文就MNKs的结构特点、作用机制、信号转导途径及其与肿瘤的密切关系进行了总结,同时详细介绍了不同研究机构报道的 MNKs抑制剂的发展过程和临床研究进展。
在单克隆抗体类免疫检查点抑制剂、嵌合抗原受体T淋巴细胞(CAR-T)疗法和过继性细胞疗法等肿瘤免疫疗法取得巨大成功后,靶向免疫系统的小分子调节剂成为了学术界关注的热点。不同于目前免疫治疗中常用的大分子生物药存在低生物利用度、价格昂贵、免疫相关不良反应(irAE)等缺点,通过小分子药物调节免疫系统具有独特的优势,这些优势可以与生物学方法互补并具有潜在的协同作
MNKs是丝氨酸/苏氨酸激酶,属于C

Figure 1 Sequence structures of splice variants of Mitogen-activated protein kinase (MAPK)-interacting kinases (MNKs)
NLS: Nuclear localization signal sequence; NES: Nuclear export signal

Figure 2 Protein crystal structure of MNK2 (PDB code: 4AC3)
DFD motif: Asp226/Phe227/Asp228
MNKs位于Ras/Raf/ERK和p38 MAPK信号通路的下游交汇处,在受到生长因子和细胞外因子的刺激后,ERK和p38 MAPK可将MNKs磷酸化激活。磷酸化后的MNKs负责多个下游底物的磷酸化,包括真核翻译起始因子4E(eIF4E)、异质核蛋白A1(hnRNP A1)、软脂酰化磷蛋白Sprouty2、PTB相关剪接因子(PSF)和细胞质磷脂酶A2(cPLA2)。eIF4E是MNKs特征最明显研究最广泛的底物,MNKs可在保守的Ser209处特异性磷酸化eIF4E,被MNKs磷酸化后的eIF4E可以识别并直接结合含有7-甲基鸟苷部分的mRNA 5′末端帽子结构。eIF4E是真核翻译起始因子复合物4F(eIF4F)的重要组成部分,是mRNA翻译的关键限速因子。eIF4F复合物由支架蛋白eIF4G、ATP依赖的RNA解旋酶eIF4A和eIF4E组成,eIF4G通过与eIF4E结合而接近mRNA,eIF4A与eIF4G结合以解开mRNA 5′末端非翻译区的二级结构,并促进核糖体结合和5'UTR的扫

Figure 3 Signal transduction pathway of Mitogen-activated protein kinase (MAPK)-interacting kinases (MNKs)
RTK: Receptor tyrosine kinase; PI3K: Phosphoinositide 3-kinase; mTORC1: Mammalian target of rapamycin complex 1; ERK: Extracellular regulated protein kinases; MKK: MAP kinase kinase; MAPK: Mitogen-activated protein kinase; eIF4E: Eukaryotic translation initiation factor 4E; PSF: Polypyrimidine tract-binding protein dependent splicing factor; hnRNP A1: Heterogeneous nuclear ribonucleoprotein A1; cPLA2: Cytoplasmic phospholipase A2
上调MNKs/eIF4E可促进多种致癌蛋白的表达,大量研究表明,eIF4E在包括乳腺
近年来,MNKs作为肿瘤治疗的靶点,受到了众多科研机构和制药公司的关注和投资。虽然到目前为止还没有小分子MNKs抑制剂药物上市,但随着对MNKs研究的深入和肿瘤免疫的兴起,新型选择性小分子MNKs抑制剂的开发也越来越受到重视。现根据在研公司和化学结构对MNKs抑制剂分类介绍。
2000年,Novartis公司首次报道了十字孢碱衍生物CGP052088(MNK1 IC50 = 70 nmol/L)可以有效抑制MNK1的活性,并阻断HEK293细胞中由eIF4E磷酸化导致的激酶级联反

2016年,Novartis公司通过高通量筛选(HTS)报道了一类氨基吡啶骨架的选择性MNKs抑制剂。化合物1(MNK1 IC50 = 0.7 μmol/L,MNK2 IC50 = 0.9 μmol/L)表现出中等的抑制活性,与MNK2(PDB: 6AC3)的对接结果显示,氨基吡啶与铰链区域形成两个氢键,苯并咪唑环与Phe159之间存在π-π相互作用(

Figure 4 Cocrystal structure of compounds in MNK2
A:Cocrystal structure of compound 1 in MNK2 (PDB:6AC3); B:Cocrystal structure of compound 4 in MNK2 (PDB: 6AC3)

2011年,Lilly公司通过HTS鉴定并报道了天然产物cercosporamide(MNK1 IC50 = 116 nmol/L,MNK2 IC50 = 11 nmol/L)是一种有效的选择性MNKs抑制剂。Cercosporamide是一种已知的广谱抗真菌药,可有效抑制多种肿瘤细胞系的eIF4E磷酸化,并减少细胞增殖,增加细胞凋亡。作为首个口服且在小鼠体内有效的MNKs抑制剂,cercosporamide可以在给药后30 min之内有效抑制肿瘤异种移植小鼠肝组织中的eIF4E磷酸化,并有效抑制HCT116异种移植模型中肿瘤增殖和B16黑色素瘤模型的肺转移瘤的生长而不引起小鼠体重降低。用cercosporamide处理急性髓系白血病(AML)细胞能够以剂量依赖性方式抑制eIF4E磷酸化,并增强阿糖胞苷(Ara-C)或哺乳动物雷帕霉素靶蛋白复合物1(mTORC1)抑制剂的抗白血病活性。在MV4-11异种移植模型中,cercosporamide能显著增强阿糖胞苷的抗肿瘤活

Bayer公司在对CGP57380吡唑并嘧啶骨架和结合模式深入研究的基础上,尝试了多种结构衍生化,报道了一系列具有高活性和选择性的吡唑并嘧啶和吡咯并嘧啶骨架的MNK1抑制剂并进行了多篇专利保护,代表化合物6(MNK1 IC50 = 44 nmol/L)和7(MNK1 IC50 = 1 nmol/L

BAY1143269(MNK1 IC50 = 40 nmol/L,MNK2 IC50 = 904 nmol/L)是Bayer公司研发的首个进入临床的MNKs抑制剂。BAY1143269(结构未公开)具有ATP竞争结合模式,于2015年3月获批进入Ⅰ期临床试验,与多西他赛联合用于非小细胞肺癌(NSCLC)的治疗。虽然该化合物的化学结构尚未公开,但其活性和功效的一些数据已被揭示。BAY1143269在体外可以抑制多种肿瘤细胞系中eIF4E的磷酸化,IC50从0.5 µmol/L提高到2.6 µmol/L,并可以阻断MNKs调节的下游靶标的表达,包括survivin,Cdc25C和cyclin B1。BAY1143269对非小细胞肺癌(NSCLC)、结直肠癌和黑色素瘤异种移植瘤模型均有显著的疗
此外,除了Bayer公司,Boehringer Ingelheim公
2013年,新加坡科技研究局(A*STAR)下属Experimental Therapeutics Centre报道了一系列含有多种中心双环骨架的双环杂环衍生物,双环结构包括咪唑[1,2-a]吡嗪、咪唑[1,2-b]吡嗪、咪唑[1,2-a]吡啶、吡唑[1,5-a]嘧啶、咪唑[4,5-c]吡啶和苯[d]咪唑。这些化合物被鉴定为有效的MNKs抑制剂,其IC50达到了微摩尔和纳摩尔水平。对这6种双环骨架进行了进一步的研究,可分为双环核心、C-3取代基和C-6取代基3个部分(化合物12)。通过改变双环核心并修饰C-3和C-6处的取代基,可以改善与MNK1/2的相互作用。双环核心N-1与MNK1的Leu127残基和MNK2的Met162残基在激酶铰链区的酰胺主链上分别形成一分子氢键,C-3取代基伸向疏水口袋,而C-6取代基占据了靠近ATP结合口袋的磷酸口袋。化合物13(MNK1 IC50 = 0.79 μmol/L,MNK2 IC50 = 0.52 μmol/L)是咪唑并吡嗪类化合物,对MNKs的抑制能力中等,但不能抑制细胞中eIF4E磷酸化。将化合物13的乙酰胺替换为4-PhCONH2 得到化合物14(MNK1 IC50 = 0.31 μmol/L,MNK2 IC50 = 0.19 μmol/L),其对MNKs的抑制活性提高了2 ~ 3倍,可能是由于Ser166的羰基和化合物侧链羟基之间存在氢键。同时,化合物14可降低细胞内eIF4E的磷酸化,并表现出良好的渗透性和体外ADME特性。当化合物14的伯酰胺被较大的酰胺取代,如用吗啉环取代,得到的化合物15(MNK1 IC50 = 0.13 μmol/L,MNK2 IC50 = 0.11 μmol/L)对MNKs的抑制活性进一步提高,且具有更好的渗透性和溶解度。在C-3处进一步的衍生化未能提高苯基取代基的效能,但与具有相似效能的类似物相比,苯甲腈的亲脂性更低,并且显示出更好的溶解性和渗透性。对双环核心的研究表明,用咪唑[1,2-a]吡啶取代咪唑[1,2-a]吡嗪对MNK1的抑制活性提高了6 ~ 9倍,对MNK2的抑制活性提高了5 ~ 7

Figure 5 Cocrystal structure of compound ETC-206 in MNK2 (PDB: 6AC3)

2014年,Experimental Therapeutics Centre还报道了一类杂芳基炔烃衍生物作为MNKs抑制剂,其可与MNKs的非活性形式(DFD-out)可逆结合。代表化合物17。此类化合物可以降低HeLa细胞中eIF4E的磷酸化水平,抑制K562细胞的增

Figure 6 Cocrystal structure of compound 18 in MNK2 (PDB: 6AC3)

2015年,eFFECTOR Therapeutics公司首次报道了具有吡啶酮-缩醛胺结构的氨基嘧啶类MNKs抑制

Figure 7 Cocrystal structure of compound eFT-508 in MNK2 (PDB: 6CK6)

2014年,Selvita S.A.公司通过小分子激酶库的筛选,报道了一类苯并氨基吡唑衍生物作为新型的选择性ATP竞争性MNKs抑制剂,它们中大多可以在低纳摩尔水平抑制MNK1和MNK2的活性。代表化合物SLV-2346(MNK1 IC50 = 10.8 nmol/L, MNK2 IC50 = 5.4 nmol/L)具有良好的选择性,并且可以在白血病、乳腺癌和前列腺癌等多种肿瘤细胞系中有效抑制eIF4E的磷酸化,且无细胞毒性现象。在胶质母细胞瘤和结直肠癌模型中,SLV-2346可以抑制eIF4E的磷酸化并显著减少肿瘤的生长和转

近年来,具有多样骨架结构的MNKs抑制剂相继得到报道,并且随着对eFT508和ETC-206等化合物临床研究的进一步深入,国内的研发机构也在积极拓展具有相似骨架的化合物。南京天印健华医药科技有限公司在2018年公开了一系列氨基嘧啶类MNKs抑制剂,其中大多化合物都可以在低纳摩尔水平抑制MNKs的活性,其中代表化合物24(MNK1 IC50 = 2.7 nmol/L

近年来,随着对MNKs在肿瘤的生长、增殖、凋亡和耐药性中重要作用的深入研究,MNKs抑制剂的开发取得了重大进展并显示出初步的临床效果,大量研究也揭示了MNKs在肿瘤免疫治疗和免疫细胞中的重要作用。本文综述了MNKs的结构、作用机制、信号转导途径及其与肿瘤的关系,并重点介绍了MNKs抑制剂的研究进展。这些研究机构在开发MNKs抑制剂方面的努力为进一步设计新型MNKs抑制剂提供了指导。尽管目前尚无靶向MNKs的药物上市,但作为调节mRNA翻译的关键激酶,其抑制剂在减少肿瘤的发生、转移、耐药和不良预后都发挥着重要的作用,还十分有望与包括CTLA-4和PD-1/PD-L1抑制剂在内的免疫治疗药物联合用药以达到更好的治疗效果。目前,除了几个进入临床的化合物外,还有多个小分子化合物处于临床前生物活性测试阶段,给药效果显著。总之,靶向MNKs以及开发有效的MNKs抑制剂具有十分广阔的发展前景。
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