张昱,翟鑫
ZHANG Yu,ZHAI Xin

• 1:沈阳药科大学基于靶点的药物设计与研究教育部重点实验室

摘要(Abstract)：

目的综述c-ros原癌基因1(c-ros oncogene 1,ROS1)酪氨酸激酶的结构和功能及其抑制剂的研究进展。方法查阅近年来国内外相关文献47篇,对其进行归纳总结和分析。结果 ROS1作为一个关键的跨膜受体蛋白酪氨酸激酶,控制细胞凋亡、生存、分化及增殖等多个细胞进程,对多种恶性肿瘤的治疗有重要作用,因此,开发ROS1抑制剂具有重要的价值。2015年4月,克唑替尼(crizotinib)被美国FDA授予突破性药物资格,用于ROS1阳性非小细胞肺癌的潜在治疗;随后2-氨基嘧啶类、4-芳氨基喹啉类等化合物相继被报道具有较强的ROS1激酶抑制活性,此外,一些选择性ROS1抑制剂(如化合物12)也被开发出来。结论尽管目前对ROS1选择性抑制剂研究较少,但ROS1抑制剂仍具有良好的开发前景。
Objective To review the research progress in identifying the structure and function of ROSl tyrosine kinase and its inhibitors.Methods The relevant 47 papers on ROSl inhibitors were reviewed and summarized.Results As a pivotal transmembrane receptor protein tyrosine kinase,ROS1 regulates several cellular processes like apoptosis,survival,differentiation and proliferation.There is increasing evidence supporting that ROSl plays an important role in different malignancies including non-small cell lung cancer(NSCLC),colorectal cancer and glioblastoma.Therefore,it is valuable to develop ROSl inhibitors.In April 2015,Crizotinib had been approved by the FDA as breakthrough therapy designation for the treatment of ROSl positive NSCLC.Then there are many kinds of scaffolds,such as 2-aminopyrimidine scaffold,4-arylaminoquinoline scaffold,have been reported as effective ROSl inhibitors.In addition,a number of selective ROSl inhibitors,such as compound 11,were developed sequentially.Conclusions As one of the important antitumor targets,ROS1 has been studied deeply.Although only a few of its selective inhibitors were developed,ROS1 still has a brilliant prospect.

关键词(KeyWords)： ROS1激酶;受体酪氨酸激酶;肿瘤;ROS1抑制剂
R0S1 kinase;receptor tyrosine kinase;cancer;ROS1 inhibitors

Abstract:

Keywords:

基金项目(Foundation): 国家自然科学基金资助项目(81673308)

作者(Author): 张昱,翟鑫
ZHANG Yu,ZHAI Xin

DOI: 10.14066/j.cnki.cn21-1349/r.2017.03.013

参考文献(References)：

• [1]SIEGEL R L,MILLER K D,JEMAL A,et al.Cancer statistics 2015[J].CA Cancer J Clin,2015,65(1):5-29.
• [2]SHIOZAWA T,ISHII G,GOTO K,et al.Clinicopathological characteristics of EGFR mutated adenosquamous carcinoma of the lung[J].Pathol Int,2013,63(2):77-84.
• [3]KWAK E L,BANG Y J,CAMIDGE D R,et al.Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer[J].N Engl J Med.2010,363(18):1693-1703.
• [4]SODA M,CHOI Y L,ENOMOTO M,et a1.Identification of the transforming EMIA-ALK fusion gene in nonsmall-cell lung cancer[J].Nature,2007,448(7153):561-566.
• [5]ROTHSCHILD S I.Targeted therapies in Non-small cell lung cancer-beyond EGFR and ALK[J].Cancers,2015,7(2):930-949.
• [6]RIKOVA K,GUO A,ZENG Q,et al.Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer[J].Cell,2007,131(6):1190-1203.
• [7]GAINOR J F,SHAW A T.Novel targets in non-small cell lung cancer:ROS1 and RET fusions[J].Oncologist,2013,18(7):865-875.
• [8]SOLOMON B.Validating ROS1 rearrangements as a therapeutic target in Non-Small-Cell Lung[J].Cancer J Clin Oncol,2015,33(9):972-974.
• [9]BIRCHMEIER C,O'NEILLK,RIGGS M,et al.Characterization of ROS1 c DNA from a human glioblastama cell line[J].Proc Natl Acad Sci U S A,1990,87(12):4799-4803.
• [10]DAVIES K D,DOEBELE R C.Molecular pathways:ROS1 fusion proteins in cancer[J].Clin Cancer Res,2013,19(15):4040-4045.
• [11]BELLACASA R P,KARACHALIOU N,TEJEDOR R,et al.ALK and ROS1 as a joint target for the treatment of lung cancer:a review[J].Transl Lung Cancer Res,2013,2(2):72-86.
• [12]BERGETHON K,SHAW A T,OU S H,et al.ROS1 rearrangements define a unique molecular class of lung cancers[J].J Clin Oncol,2012,30(8):863-870.
• [13]SHAW A T,CAMIDGE D R,ENGELMAN J A,et al.Clinical activity of crizotinib in advanced non-small cell lung cancer(NSCLC)harboring ROS1 gene rearrangement[J].Ann Oncol,2012,30(9):33.
• [14]SHAW A T,KIM D W,NAKAGAWA K,et al.Crizotinib versus chemotherapy in advanced ALK-positive lung cancer[J].N Engl J Med,2013,368(25):2385
• [15]AWAD M M,KATAYAMA R,MCTIGUE M,et al.Acquired resistance to cirzotinib from a mutation in CD74-ROS1[J].N Engl J Med,2013,369(12):1172-1173.
• [16]FRIBOULET L,LI N X,KATAYAMA R,et al.The ALK inhibitor Ceritinib overcomes Crizotinib resistance in non-small cell lung cancer[J].Cancer Discov,2014,4(6):662-673.
• [17]SOLOMON B.Validating ROS1 rearrangements as a therapeutic target in Non-Small-Cell Lung Cancer[J].J Clin Oncol,2015,33(9):972-974.
• [18]GALKIN A V,MELNICK J S,KIM S,et al.Identification of NVP-TAE684,a potent,selective,and efficacious inhibitor of NPM-ALK[J].Proc Natl Acad Sci,2007,104(1):270-275.
• [19]MEHRA R,CAMIDGE D R,SHARMA S,et al.Results of a first-in-human phase I study of the ALK inhibitor LDK378 in advanced solid tumors[J].J Clin Oncol,2012,30(Suppl):A3007.
• [20]LIANG S,HONG F J.Ceritinib in ALK-rearranged non-small-cell lung cancer[J].N Engl J Med,2014,370(26):2537-2539.
• [21]KATAYAMA R,KHAN T M,BENES C,et al.Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4-ALK[J].Proc Natl Acad Sci U S A,2011,108(18):7535-7540.
• [22]AQUILA B,KAMHI V,PENG B,et al.Chemical compounds,2012017239(A1)[P],2012-02-09.
• [23]CHIN L P,SOO R A,SOONG R,et al.Targeting ROS1with anaplastic lymphoma kinase inhibitors:a promising therapeutic strategy for a newly defined molecular subset of non-small-cell lung cancer[J].J Thorac Oncol,2012,7(11):1625-1630.
• [24]MARSILJE T H,PEI W,CHEN B,et al.Synthesis,structure-activity relationships,and in vivo efficacy of the novel potent and selective anaplastic lymphoma kinase(ALK)Inhibitor5 Chloro N2(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)N4(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine(LDK378)currently in phase 1 and phase 2 clinical trials[J].J Med Chem,2013,56(14):5675-5690.
• [25]YAMAZAKI S,LAM J L,ZOU H Y,et al.Translational pharmacokinetic pharmacodynamic modeling for an orally available novel inhibitor of anaplastic lymphoma kinase and c-Ros oncogene 1[J].J Pharmacol Exp Ther,2014,351(1):67-76.
• [26]TED W J,PAUL F R N,SIMON B,et al.Discovery of(10R)7-Amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H 8,4-(metheno)pyrazolo[4,3 h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile(PF-06463922),a Macrocyclic Inhibitor of Anaplastic Lymphoma Kinase(ALK)and cros Oncogene 1(ROS1)with Preclinical Brain Exposure and Broad Spectrum Potency against ALK-Resistant Mutations[J].J Med Chem,2014,57(11):4720-4744.
• [27]ZOU H Y,LI Q,ENGSTROM L D,et al.PF-06463922is a potent and selective next-generation ROS1/ALK inhibitor capable of blocking crizotinib-resistant ROS1mutations[J].Proc Natl Acad Sci,2015,112(11):3493-3498.
• [28]MONIKA A D,ANNA S,CHRISTOPHER A E,et al.Foretinib is a potent inhibitor of oncogenic ROS1[J].Proc Natl Acad Sci,2013,110(8):19519-19524.
• [29]KOIVUNEN J P,MERMEL C,ZEJNULLAHU K.EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer[J].Clin Cancer Res,2008,14(13):4275-4283.
• [30]RYOHEI K,YUKA K,LUC F,et al.Cabozantinib overcomes crizotinib resistance in ROS1 fusion-positive cancer[J].Clin Cancer Res,2 0 1 5,2 1(1):1 6 6-1 7 4.
• [31]ARDINI E,MENICHINCHERI M,DE P C,et al.Characterization of NMS-E6 2 8,a small molecule inhibitor of anaplastic lymphoma kinase with antitumor efficacy in ALK-dependent lymphoma and nonsmall cell lung cancer models[J].Mol Cancer Ther,2 0 0 9,8:A2 4 4.
• [32]IVANA S,DAVID P.ALK inhibitors in non-small cell lung cancer:the latest evidence and developments[J].Ther Adv Med Oncol,2016,8(1):32-47.
• [33]MARIA M,ELENA A,PAOLA M,et al.Discovery of Entrectinib:a new 3-aminoindazole as a potent Anaplastic Lymphoma Kinase(ALK),c-ros Oncogene 1 Kinase(ROS1),and Pan-Tropomyosin Receptor Kinases(Pan-TRKs)inhibitor[J].J Med Chem,2016,59(7):3392-3408.
• [34]MORI M,UENO Y,KONAGAI S,et al.Study of an investigational drug,ASP3026,in patients with advanced malignancies(solid tumors and B-cell lymphoma)(NCT01284192)[EB/OL].[2011-02-13].https://clinicaltrials.gov/show/NCT01284192.
• [35]MORI M,UENO Y,KONAGAI S,et al.The selective anaplastic lymphoma receptor tyrosine kinase inhibitor ASP3026 induces tumor regression and prolongs surviv al in non-small cell lung cancer model mice[J].Mol Cancer Ther,2014,13(2):329-340.
• [36]CHIN L P,SOO R A,SOONG R,et al.Targeting ROS1with anaplastic lymphoma kinase inhibitors:a promising therapeutic strategy for a newly defined molecular subset of non-small-cell lung cancer[J].J Thorac Oncol,2012,7(11):1625-1630.
• [37]BOSSI R T,SACCARDO M B,ARDINI E,et al.Crystal structures of anaplastic lymphoma kinase in complex with ATP competitive inhibitors[J].Biochemistry,2010,49(32):6813-6825.
• [38]A first-in-human study to evaluate the safety,tolerability and pharmacokinetics of DS-6051b(NCT02279433)[EB/OL].[2014-11-03].https://clinicaltrials.gov/show/NCT02279433.
• [39]PARK B S,EL-DEEB I M,YOO K H,et al.Design,synthesis and biological evaluation of new potent and highly selective ROS1-tyrosine kinase inhibitor[J].Bioorg Med Chem Lett,2009,19(16):4720-4723.
• [40]PARK B S,AL-SANEA M M,ABDELAZEM A Z,et al.Structure-based optimization and biological evaluation of trisubstituted pyrazole as a core structure of potent ROS1 kinase inhibitors[J].Bioorgan Med Chem,2014,22(15):3871-3878.
• [41]SANEA M M,ABDELAZEM A Z,PARK B S,et al.ROS1 Kinase Inhibitors for Molecular-Targeted Therapies[J].Curr Med Chem,2016,23(2):142-160.
• [42]ITSURO S,TAKAHIRO M,KAZUO K,et al.Arylaminoheterocyclic carboxamide compound:2012053606[P].2012-04-26.
• [43]TAKEDA Y,YOSHILKAWA K,KAGOSHIMA Y,et al.Imidazo[1,2-b]pyridazine derivative as kinase inhibitor:2013183578 A1[P].2013-12-12.
• [44]LIU J,MAO L,WANG X,et al.Pyrazolopyrimidine derivatives and uses as anticancer agents:2012097196 A1[P].2012-07-19.
• [45]XIONG Y,CONNOLLY T,FUTCHER B,et al.Human D-type cyclin[J].Cell,1991,65(4):691-699.
• [46]GREGOR V E,LEVY N.Tyrosine kinase inhibitors:20120065233 A1[P].2012-03-15.
• [47]NOGAWA M.Ros tyrosine kinase inhibitor:2012005299 A1[P].2012-01-12.