摘要
细胞外信号调节激酶(ERK)是一种丝/苏氨酸蛋白激酶。作为RAS-RAF-MEK-ERK信号通路中关键的下游蛋白,其异常活化在肿瘤的发生发展中起着重要作用。选择性ERK1/2抑制剂能够阻断ERK信号通路,同时克服上游靶点突变而导致的耐药性。本文概述了MAPK信号通路的组成、ERK的结构与功能以及ERK信号通路在肿瘤发生发展中的作用,并重点介绍一些具有代表性的处于临床和临床前研究阶段的ERK抑制剂。
RAS-RAF-MEK-ERK信号通路是一条广泛存在于哺乳动物细胞中的信号级联通路,在细胞的分化、存活、衰老和凋亡等细胞活动中发挥着极其重要的作
丝裂原活化蛋白激酶(mitogen-activated protein kinases, MAPKs)信号通路可以将细胞外信号转导至细胞内,从而调节各种生物学功

图1 哺乳动物体内的MAPKs信号传导通路
ASK: 凋亡信号调节激酶(apoptosis signal-regulation kinase); MAPKKK: 丝裂原活化蛋白激酶激酶激酶(mitogen-activated protein kinase kinase kinase); MAPKK: 丝裂原活化蛋白激酶激酶(mitogen-activated protein kinase kinase); MAPK: 丝裂原活化蛋白激酶(mitogen-activated protein kinase); MLKs: 混合谱系激酶(mixed lineage kinases); MK: 丝裂原活化蛋白激酶激活蛋白激酶(MAPK-activated protein kinase); PAKs: p21活化的激酶(p21-activated kinases)
RAS-RAF-MEK-ERK信号通路具有高度的保守

图2 RAS-RAF-MEK-ERK信号通路
GEFs: 鸟苷酸交换因子(guanine nucleotide exchange factors); GPCR: G蛋白偶联受体(G protein coupled receptor); GRB2: 生长因子受体结合蛋白2 (growth factor receptor bound protein 2); RTK: 受体酪氨酸激酶(receptor tyrosine kinase); SOS:son of sevenless homolog
与其他蛋白激酶类似,ERK蛋白也具有由N端和C端卷曲形成的双叶结构。其N端由5股反向平行的β片层结构(β1~β5)、1个αC螺旋结构和一个甘氨酸富集环结构组成,C端则由6个保守的α螺旋结构和4股较短的β片层结构(β6~β9)组

图3 ERK2的二级结构 (PDB:2OJJ)
几乎所有的哺乳动物体内都有ERK蛋白的表达。到目前为止,ERK蛋白被鉴定出有两个亚型:ERK1和ERK
目前,已知的ERK底物数量多达上百种,主要分布在细胞膜、细胞质以及细胞核。ERK1/2在细胞质底物包括RSK家族蛋白激酶、磷蛋白磷酸酶、cAMP磷酸二酯酶、胞浆磷脂酶A2、细胞骨架蛋白
在约30%的肿瘤中,RAS-RAF-MEK-ERK信号通路均处于异常激活状态。该信号通路中各成员蛋白的突变和异常表达在多种恶性肿瘤的发生发展过程中都发挥了重要作用。例如:在约1/3的肿瘤中存在RAS的突变激活,其中KRAS的突变比率最高,占人类肿瘤总数的20%以上,在前列腺癌中的突变比率更是高达90
因此,针对RAS-RAF-MEK-ERK信号通路研发的小分子靶向药物无疑在抗肿瘤药物研究领域占有突出地
目前,已有多个BRAF抑制剂和MEK抑制剂被美国FDA批准上市,用于治疗各种实体瘤,在临床治疗中取得了良好的效果。如:BRAF抑制剂索拉非尼(sorafenib)、维罗非尼(vemurafenib)和达拉非尼(dabrafenib);MEK抑制剂曲美替尼(trametinib)、司美替尼(selumetinib)和考比替尼(cobimetinib)。虽然在患者接受治疗的初期,肿瘤的发展进程得到了有效控制,但是在长时间服用该类靶向药物后,肿瘤细胞不可避免的产生了获得性耐药。与RAS、BRAF等在肿瘤细胞中的高突变率不同,到目前为止,ERK1/2的获得性突变在肿瘤细胞中几乎没有出
因此,与抑制MAPK信号通路中的上游靶点相比,抑制下游的ERK同样能够起到阻断细胞信号转导的作用。更为重要的是,ERK抑制剂能够克服肿瘤细胞对RAF抑制剂和MEK抑制剂的耐药性,在临床上具有更广泛的应用前景。
鉴于在肿瘤的发生发展过程中,MAPK信号通路发挥了重要作用,而ERK激酶又是MAPK信号通路中十分关键的下游靶点。因此,选择性抑制ERK能够阻断MAPK信号通路,同时逆转上游靶点突变产生的耐药性。虽然目前尚无ERK1/2抑制剂被正式批准上市,但是已经有一些小分子ERK抑制剂处于临床或临床前研究阶段,下面将重点介绍小分子ERK抑制剂的研究进展。
近年来,已有多个ERK抑制剂进入临床研究,包括GDC-0994(1)、Ulixertinib(BVD-523)(2)、KO-947(3)、LY3214996(4)、MK-8353(5)、CC-90003(6)、LTT462等。

GDC-0994 (1)是由Genentech公司研发的口服的选择性ERK1/2抑制剂,其对ERK1和ERK2的IC50分别为6.1和3.1 nmol/L。
2014年,Genentech公司通过高通量筛选得到四氢吡啶并嘧啶类化合物7,其对ERK2的IC50为106 nmol/L。以化合物7为先导化合物,经过结构优化得到化合物8,其对ERK2的IC50提高到 2 nmol/L,并且在人HCT116结直肠癌的裸鼠移植模型中表现出较好的抗肿瘤效

分析GDC-0994与ERK2的共晶复合物(

图4 化合物GDC-0994与ERK2的共晶复合
动物实验结果表明,在HCT116小鼠移植瘤模型中,GDC-0994能够显著降低p90RSK的磷酸化水平,抑制肿瘤组织的生长。在临床前的安全性评价试验中,与其他MEK和ERK抑制剂类似,GDC-0994也表现出一些不良反应,包括大鼠体内由磷失调引发的软组织矿化、白蛋白水平下调和皮肤毒性、以及犬的胃肠道毒性
目前,GDC-0994用于治疗局部晚期或转移性实体瘤的Ⅰ期临床试验已经结束,进一步的临床研究暂无报道。
Ulixertinib(BVD-523,VRT752271, 2)是由BioMed Valley Discoveries公司研发的可逆型ATP竞争性ERK1/2抑制剂,其对ERK1的Ki < 0.3 nmol/L,对ERK2的Ki = 0.04 nmol/L。无论是对活化的ERK2(pERK2)还是非活化的ERK2,Ulixertinib均表现出强亲和力,但是对pERK2的亲和力要强于非活化的ERK2。
体外细胞实验结果显示,在BRA
目前,Ulixertinib单独用药治疗晚期恶性肿瘤正处于Ⅱ期临床研究阶段(NCT01781429),用于治疗急性骨髓性白血病和骨髓增生异常综合征正处于Ⅰ/Ⅱ期临床研究阶段(NCT02296242)。在药物联用方面,Ulixertinib与白蛋白结合型紫杉醇(nab-paclitaxel)和吉西他滨(gemcitabine)联合应用治疗转移性胰腺癌正处于Ⅰ期临床研究阶段(NCT02608229),与CDK4/6抑制剂哌柏西利(palbociclib)联合应用治疗晚期胰腺癌和其他实体瘤正处于Ⅰ期临床研究阶段(NCT03454035)。
LY3214996(4)是由礼来公司研发的口服的ERK1/2抑制剂(IC50 = 5 nmol/L),在BRAF和RAS突变的肿瘤细胞中可以抑制RSK1的磷酸化水平。2016年作为治疗晚期实体瘤的药物进入Ⅰ期临床研究。其除了可以单独用药外,还可以与其他抗肿瘤药物联合使用,比如与CDK4/6抑制剂、PI3K/mTOR 抑制剂联用治疗RAS突变的非小细胞型肺
MK-8353(5)是通过改善SCH772984的PK而优化得到的(ERK1:IC50 = 20 nmol/L; ERK2:IC50 = 7 nmol/L)。SCH772984是由Merck公司通过基于亲和力的质谱高通量平台筛选、鉴定并通过结构优化得到的ATP竞争性的ERK1/2抑制剂。分析共晶结构,发现吲唑环与铰链区的Asp104与Met106形成至关重要的氢键作用,吡咯烷与Lys52形成另一个关键的氢键,同时P-loop结构中的Tyr34残基翻转到ATP位点并堆叠到吡咯烷环的上方,导致P-loop结构发生扭曲,P-loop结合口袋被打开产生一个可以被甲基取代的三唑环占据的空腔。这些结论也表明,MK-8353对ERK的高选择性主要是通过变构抑制的方式实现
除了上述介绍的已经进入临床的化合物,目前还有很多的ERK抑制剂处于临床前阶段或生物活性评价阶段。这些化合物主要包括FR180204(11)、VTX-11e(12)、BL-EI-001(13)。

Ohori
通过分析FR180204与ERK2的共晶复合物(

图5 FR180204与ERK2的共晶复合物 (PDB:1TVO)
在Mv1Lu貂肺上皮细胞中,FR180204能够剂量依赖性地抑制TGFβ诱导的AP-1的激活,其IC50为3.1 μmol/L。动物实验结果表明,在CIA小鼠模型中,FR180204能够明显改善关节炎症状并恢复体重损
目前,FR180204仍处于临床前的研究阶段,未见相关的临床试验报道。
Vertex制药公


图6 化合物与ERK2的共晶复合物和叠合图
A: 化合物14与ERK2的共晶复合
为了提高化合物的细胞活性,将化合物15结构中与铰链区有相互作用的吡唑环替换为氨基嘧啶环,增强了化合物与铰链区的氢键作用,得到了先导化合物16。但是通过分析共晶结构(
为了提高先导化合物16对ERK的选择性,研究人员对苯胺部分和苯基甘氨醇部分进行结构优化,最终得到化合物VTX-11e(12)。VTX-11e是有效的高选择性ERK2抑制剂,其对ERK2的Ki小于 2.0 nmol/L,对GSK3、AuroraA和CDK2有200倍以上的选择性,对受测的其他激酶的选择性更是大于500
体外细胞研究结果显示,在HT29人结肠癌细胞增殖测试中,VX-11e的IC50为48 nmol/L。体内研究结果显示,在大鼠和小鼠中,VX-11e表现出较好的口服生物利用度。在对BRAF/MEK抑制剂联合治疗和PI3K抑制剂单独治疗均有耐药性的人黑色素瘤移植的NSG小鼠模型中,单独使用VX-11e能够抑制肿瘤组织生长;当与PI3K抑制剂BKM120联用时,能够明显抑制肿瘤生
目前,VX-11e仍处于临床前的生物活性测试阶段。
BL-EI-001(13)是由清华大学、四川大学、沈阳药科大学联合开发的ERK抑制剂,其设计策略是基于结构的药物设计,通过分子对接筛选DrugBank和ZINC得到了打分最高的11个化合物,然后通过生物活性测试确定先导化合物后再进行结构优化从而发现了BL-EI-001。通过对接发现疏水基团苯环与氨基酸残基Ile48、Val56、Ala69 和Met125形成疏水作用,同时BL-EI-001可以与Lys71形成两个氢键作用,与Tyr53形成两个π-π作用。然而BL-EI-001对肿瘤的抑制作用不是通过Ras/Raf/MEK1/2通路,而是通过线粒体通路来发挥抗肿瘤作
到目前为止,已有多个RAF抑制剂和MEK抑制剂应用于临床并取得了较好的肿瘤治疗效果。但是,在长期服用该类药物治疗肿瘤的过程中,不可避免的产生了耐药性问题。在对肿瘤耐药机制的研究中发现,原本被抑制的RAS-RAF-MEK-ERK信号通路被重新激活,其主要原因是RAF和MEK的突变导致其对现有药物治疗的不敏感,从而引起患者肿瘤复发,治疗失败。本课题组通过骨架跃迁的药物设计策略,发现了一类异吲哚-1-酮类化合物对ERK具有较好的抑制作用,在KRAS和BRAF突变的肿瘤中体现出良好的抗增殖活
虽然与RAF和MEK抑制剂深入的研究进展相比,ERK抑制剂的研发较为滞后,但是以ERK为靶点来特异性阻断RAS-RAF-MEK-ERK信号通路的药物研发策略正越来越受到人们的重视。目前,已有多个ERK抑制剂处于临床或临床前研究阶段。
随着ERK抑制剂的不断研发以及临床研究的逐步深入,ERK抑制剂有望成为继RAF抑制剂和MEK抑制剂之后的新一代MAPK信号通路相关药物,克服RAF抑制剂和MEK抑制剂的耐药性问题,并在肿瘤的临床治疗方面产生积极而深远的影响。
参考文献
Liu QH, Shi ML, Sun C, et al. Role of the ERK1/2 pathway in tumor chemoresistance and tumor therapy[J]. Bioorg Med Chem Lett, 2015, 25(2): 192-197. [百度学术]
Wang X, Zhang PH. Advances in research on the modulation of autophagy by Ras/Raf/MEK/ERK signaling pathway[J]. J China Pharm Univ(中国药科大学学报), 2017, 48(1): 110-116. [百度学术]
Samatar AA, Poulikakos PI. Targeting RAS-ERK signalling in cancer: promises and challenges[J]. Nat Rev Drug Discov, 2014, 13(12): 928-942. [百度学术]
Yu ZT, Ye SQ, Hu GY, et al. The RAF-MEK-ERK pathway: targeting ERK to overcome obstacles to effective cancer therapy[J]. Future Med Chem, 2015, 7(3): 269-289. [百度学术]
Uehling DE, Harris PA. Recent progress on MAP kinase pathway inhibitors[J]. Bioorg Med Chem Lett, 2015, 25(19): 4047-4056. [百度学术]
Menon MB, Gaestel M. TPL2 meets p38MAPK: emergence of a novel positive feedback loop in inflammation[J]. Biochem J, 2016, 473(19): 2995-2999. [百度学术]
Lei ZY, van Mil A, Brandt MM, et al. MicroRNA-132/212 family enhances arteriogenesis after hindlimb ischaemia through modulation of the Ras-MAPK pathway[J]. J Cell Mol Med, 2015, 19(8): 1994-2005. [百度学术]
Kim EK, Choi EJ. Compromised MAPK signaling in human diseases: an update[J]. Arch Toxicol, 2015, 89(6): 867-882. [百度学术]
Asati V, Mahapatra DK, Bharti SK. PI3K/Akt/mTOR and Ras/Raf/MEK/ERK signaling pathways inhibitors as anticancer agents: Structural and pharmacological perspectives[J]. Eur J Med Chem, 2016, 109: 314-341. [百度学术]
Caunt CJ, Sale MJ, Smith PD, et al. MEK1 and MEK2 inhibitors and cancer therapy: the long and winding road[J]. Nat Rev Cancer, 2015, 15(10): 577-592. [百度学术]
Simanshu DK, Nissley DV, McCormick F. RAS proteins and their regulators in human disease[J]. Cell, 2017, 170(1): 17-33. [百度学术]
JrRoskoski R. A historical overview of protein kinases and their targeted small molecule inhibitors[J]. Pharmacol Res, 2015, 100: 1-23. [百度学术]
Lavoie H, Therrien M. Regulation of RAF protein kinases in ERK signalling[J]. Nat Rev Mol Cell Biol, 2015, 16(5): 281-298. [百度学术]
An S, Yang Y, Ward R, et al. Raf-interactome in tuning the complexity and diversity of Raf function[J]. FEBS J, 2015, 282(1): 32-53. [百度学术]
Cseh B, Doma E, Baccarini M. “RAF” neighborhood: protein-protein interaction in the Raf/Mek/Erk pathway[J]. FEBS Lett, 2014, 588(15): 2398-2406. [百度学术]
Okumura S, Jänne PA. Molecular pathways: the basis for rational combination using MEK inhibitors in KRAS-mutant cancers[J]. Clin Cancer Res, 2014, 20(16): 4193-4199. [百度学术]
Taylor SS, Kornev AP. Protein kinases: evolution of dynamic regulatory proteins[J]. Trends Biochem Sci, 2011, 36(2): 65-77. [百度学术]
Buscà R, Christen R, Lovern M, et al. ERK1 and ERK2 present functional redundancy in tetrapods despite higher evolution rate of ERK1[J]. BMC Evol Biol, 2015, 15: 179. [百度学术]
Kidger AM, Sipthorp J, Cook SJ. ERK1/2 inhibitors: New weapons to inhibit the RAS-regulated RAF-MEK1/2-ERK1/2 pathway[J]. Pharmacol Ther, 2018, 187: 45-60. [百度学术]
JrRoskoski R. ERK1/2 MAP kinases: structure, function, and regulation[J]. Pharmacol Res, 2012, 66(2): 105-143. [百度学术]
Buscà R, Pouysségur J, Lenormand P. ERK1 and ERK2 map kinases: specific roles or functional redundancy[J]? Front Cell Dev Biol, 2016, 4: 53. [百度学术]
Yoon S, Seger R. The extracellular signal-regulated kinase: multiple substrates regulate diverse cellular functions[J]. Growth Factors, 2006, 24(1): 21-44. [百度学术]
Houles T, Roux PP. Defining the role of the RSK isoforms in cancer[J]. Semin Cancer Biol, 2018, 48: 53-61. [百度学术]
Casalvieri KA, Matheson CJ, Backos DS, et al. Selective targeting of RSK isoforms in cancer[J]. Trends Cancer, 2017, 3(4): 302-312. [百度学术]
Asano E, Maeda M, Hasegawa H, et al. Role of palladin phosphorylation by extracellular signal-regulated kinase in cell migration[J]. PLoS One, 2011, 6(12): e29338. [百度学术]
Plotnikov A, Zehorai E, Procaccia S, et al. The MAPK cascades: signaling components, nuclear roles and mechanisms of nuclear translocation[J]. Biochim Biophys Acta, 2011, 1813(9): 1619-1633. [百度学术]
Hobbs GA, der CJ, Rossman KL. RAS isoforms and mutations in cancer at a glance[J]. J Cell Sci, 2016, 129(7): 1287-1292. [百度学术]
Holderfield M, Deuker MM, McCormick F, et al. Targeting RAF kinases for cancer therapy: BRAF-mutated melanoma and beyond[J]. Nat Rev Cancer, 2014, 14(7): 455--467. [百度学术]
Jetschke K, Viehweger H, Freesmeyer M, et al. Primary pineal malignant melanoma with B-Raf V600E mutation: a case report and brief review of the literature[J]. Acta Neurochir (Wien), 2015, 157(7): 1267-1270. [百度学术]
Sogabe S, Togashi Y, Kato H, et al. MEK inhibitor for gastric cancer with MEK1 gene mutations[J]. Mol Cancer Ther, 2014, 13(12): 3098-3106. [百度学术]
Nikolaev SI, Rimoldi D, Iseli C, et al. Exome sequencing identifies recurrent somatic MAP2K1 and MAP2K2 mutations in melanoma[J]. Nat Genet, 2011, 44(2): 133-139. [百度学术]
Murugan AK, Dong JL, Xie JW, et al. MEK1 mutations, but not ERK2 mutations, occur in melanomas and colon carcinomas, but none in thyroid carcinomas[J]. Cell Cycle, 2009, 8(13): 2122-2124. [百度学术]
Arcila ME, Drilon A, Sylvester BE, et al. MAP2K1 (MEK1) mutations define a distinct subset of lung adenocarcinoma associated with smoking[J]. Clin Cancer Res, 2015, 21(8): 1935-1943. [百度学术]
JrRoskoski R. Targeting ERK1/2 protein-serine/threonine kinases in human cancers[J]. Pharmacol Res, 2019, 142: 151-168. [百度学术]
Jaiswal BS, Durinck S, Stawiski EW, et al. ERK mutations and amplification confer resistance to ERK-inhibitor therapy[J]. Clin Cancer Res, 2018, 24(16): 4044-4055. [百度学术]
Qin JZ, Xin H, Nickoloff BJ. Specifically targeting ERK1 or ERK2 kills melanoma cells[J]. J Transl Med, 2012, 10: 15. [百度学术]
Hatzivassiliou G, Liu B, O'Brien C, et al. ERK inhibition overcomes acquired resistance to MEK inhibitors[J]. Mol Cancer Ther, 2012, 11(5): 1143-1154. [百度学术]
Blake JF, Gaudino JJ, De Meese J, et al. Discovery of 5, 6, 7, 8-tetrahydropyrido[3, 4-d]pyrimidine inhibitors of Erk2[J]. Bioorg Med Chem Lett, 2014, 24(12): 2635-2639. [百度学术]
Ren L, Grina J, Moreno D, et al. Discovery of highly potent, selective, and efficacious small molecule inhibitors of ERK1/2[J]. J Med Chem, 2015, 58(4): 1976-1991. [百度学术]
Blake JF, Burkard M, Chan J, et al. Discovery of (S)-1-(1-(4-Chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (GDC-0994), an extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitor in early clinical development[J]. J Med Chem, 2016, 59(12): 5650-5660. [百度学术]
Germann UA, Furey BF, Markland W, et al. Targeting the MAPK signaling pathway in cancer: promising preclinical activity with the novel selective ERK1/2 inhibitor BVD-523 (ulixertinib)[J]. Mol Cancer Ther, 2017, 16(11): 2351-2363. [百度学术]
Germann U, Furey B, Roix J, et al. The selective ERK inhibitor BVD-523 is active in models of MAPK pathway-dependent cancers, including those with intrinsic and acquired drug resistance[J]. Cancer Res, 2015, 75: 4693. [百度学术]
U.S. National Library of Meidcine. A study of LYA3214996 administered alone or in combination with other agents in participants with advanced/metastatic cancer[EB/OL]. (2019-09-17)[2019-03-14].https://clinicaltrials.gov/ct2/show/NCT02857270. [百度学术]
Chaikuad A, Tacconi EM, Zimmer J, et al. A unique inhibitor binding site in ERK1/2 is associated with slow binding kinetics[J]. Nat Chem Biol, 2014, 10(10): 853-860. [百度学术]
Boga SB, Deng YQ, Zhu L, et al. MK-8353: discovery of an orally bioavailable dual mechanism ERK inhibitor for oncology[J]. ACS Med Chem Lett, 2018, 9(7): 761-767. [百度学术]
U.S. National Library of Meidcine. Study of MK-8353 in combination with pembrolizumab (MK-3475) in participants with advanced malignancies (MK-8353-013)[EB/OL]. (2019-07-23[2019-03-14].https://clinicaltrials.gov/ct2/show/ CT02972034. [百度学术]
U.S. National Library of Meidcine. Study of MK-8353 + Selumetinib in Advanced/Metastatic Solid Tumors (MK-8353-014)[EB/OL]. (2019-07-22)[2019-03-14]. https://clinicaltrials.gov/ct2/show/ NCT03745 989. [百度学术]
U.S. National Library of Meidcine. Safety and PK Study of CC-90003 in Relapsed/Refractory Solid Tumors[EB/OL]. (2016-08-22)[2019-03-14]. https://clinical trials.gov/ct2/show/NCT02313012. [百度学术]
Aronchik I, Dai YM, Labenski M, et al. Efficacy of a covalent ERK1/2 inhibitor, CC-90003, in KRAS-mutant cancer models reveals novel mechanisms of response and resistance[J]. Mol Cancer Res, 2019, 17(2): 642-654. [百度学术]
Ohori M, Kinoshita T, Okubo M, et al. Identification of a selective ERK inhibitor and s tructural determination of the inhibitor-ERK2 complex[J]. Biochem Biophys Res Commun, 2005, 336(1): 357-363. [百度学术]
Ohori M, Takeuchi M, Maruki R, et al. FR180204, a novel and selective inhibitor of extracellular signal-regulated kinase, ameliorates collagen-induced arthritis in mice[J]. Naunyn Schmiedebergs Arch Pharmacol, 2007, 374(4): 311-316. [百度学术]
Sreekanth GP, Chuncharunee A, Sirimontaporn A, et al. Role of ERK1/2 signaling in dengue virus-induced liver injury[J]. Virus Res, 2014, 188: 15-26. [百度学术]
Aronov AM, Baker C, Bemis GW, et al. Flipped out: structure-guided design of selective pyrazolylpyrrole ERK inhibitors[J]. J Med Chem, 2007, 50(6): 1280-1287. [百度学术]
Aronov AM, Tang Q, Martinez-Botella G, et al. Structure-guided design of potent and selective pyrimidylpyrrole inhibitors of extracellular signal-regulated kinase (ERK) using conformational control[J]. J Med Chem, 2009, 52(20): 6362-6368. [百度学术]
Krepler C, Xiao M, Sproesser K, et al. Personalized preclinical trials in BRAF inhibitor-resistant patient-derived xenograft models identify second-line combination therapies[J]. Clin Cancer Res, 2016, 22(7): 1592-1602. [百度学术]
Liu B, Fu LL, Zhang C, et al. Computational design, chemical synthesis, and biological evaluation of a novel ERK inhibitor (BL-EI001) with apoptosis-inducing mechanisms in breast cancer[J]. Oncotarget, 2015, 6(9): 6762-6775. [百度学术]
Ji DZ, Zhang LZ, Zhu QH, et al. Discovery of potent, orally bioavailable ERK1/2 inhibitors with isoindolin-1-one structure by structure-based drug design[J]. Eur J Med Chem, 2019, 164: 334-341. [百度学术]