Review Article

细胞周期蛋白依赖激酶2在细胞衰老和癌症中的作用。结构和功能审查

卷 20, 期 7, 2019

页: [716 - 726] 页: 11

弟呕挨: 10.2174/1389450120666181204165344

价格: $65

conference banner
摘要

背景:细胞周期蛋白依赖激酶2(CDK2)因其在细胞周期进程中的作用而被研究。通过晶体学和功能学的协同研究,阐明了CDK2的结构为研究抑制这种酶的分子基础奠定了基础。 目的:我们的目标是回顾最近的功能和结构研究,以了解CDK2在癌症和衰老中的作用。 方法:CDK2的晶体结构有四百多个,其中许多具有结合亲和力信息。我们利用这些丰富的数据分析了抑制CDK2的基本特征及其在癌症和衰老中的作用。 结果:CDK2的结构和亲和力数据使我们能够清楚地了解参与分子识别的重要CDK2残基。对配体结合的结构基础进行详细的描述,对CDK2抑制剂的设计具有重要意义。我们的分析显示了LEU83和ASP 86残基对结合亲和力的相关性。最近的发现揭示了CDK2抑制在衰老中的参与,为探索以细胞衰老为目标的CDK2抑制剂的发展新时代的结构和亲和力数据的丰富性提供了可能。 结论:我们结合抑制剂分析了CDK2的结构信息,并绘制了最强的CDK2抑制剂的分子结构和配体结合亲和力数据。从这个分析中,我们确定了重要的分子间相互作用负责结合亲和力。这一知识可指导针对癌症和细胞衰老的CDK2抑制剂的未来发展。

关键词: CDK2,细胞周期蛋白,细胞衰老,蛋白-配体相互作用,药物设计,癌症。

图形摘要
[1]
Sausville EA, Johnson J, Alley M, Zaharevitz D, Senderowicz AM. Inhibition of CDKs as a therapeutic modality. Ann N Y Acad Sci 2000; 910(1): 207-22.
[2]
Babu PJ, Narasub ML, Srinivasc K. Pyridines, pyridazines and guanines as CDK2 inhibitors: a review. Arkivoc 2007; 2007(2): 247-65.
[3]
Malumbres M. Cyclin-dependent kinases. Genome Biol 2014; 15(6): 122.
[4]
Chohan TA, Qian H, Pan Y, Chen JZ. Cyclin-dependent kinase-2 as a target for cancer therapy: progress in the development of CDK2 inhibitors as anti-cancer agents. Curr Med Chem 2015; 22(2): 237-63.
[5]
Malumbres M, Barbacid M. Cell cycle kinases in cancer. Curr Opin Genet Dev 2007; 17(1): 60-5.
[6]
Canavese M, Santo L, Raje N. Cyclin dependent kinases in cancer: potential for therapeutic intervention. Cancer Biol Ther 2012; 13(7): 451-7.
[7]
Criscitiello C, Viale G, Esposito A, Curigliano G. Dinaciclib for the treatment of breast cancer. Expert Opin Investig Drugs 2014; 23(9): 1305-12.
[8]
Kumar SK, LaPlant B, Chng WJ, et al. Dinaciclib, a novel CDK inhibitor, demonstrates encouraging single-agent activity in patients with relapsed multiple myeloma. Blood 2015; 125(3): 443-8.
[9]
Krenning L, Feringa FM, Shaltiel IA, van den Berg J, Medema RH. Transient activation of p53 in G2 phase is sufficient to induce senescence. Mol Cell 2014; 55(1): 59-72.
[10]
Müllers E, Silva Cascales H, Jaiswal H, Saurin AT, Lindqvist A. Nuclear translocation of Cyclin B1 marks the restriction point for terminal cell cycle exit in G2 phase. Cell Cycle 2014; 13: 2733-43.
[11]
Cascales HS, Müllers E, Lindqvist A. How the cell cycle enforces senescence. Aging 2017; 9(10): 2022-3.
[12]
Jaiswal H, Benada J, Müllers E, et al. ATM/Wip1 activities at chromatin control Plk1 re-activation to determine G2 checkpoint duration. EMBO J 2017; 36(14): 2161-76.
[13]
Wadler S. Perspectives for cancer therapies with cdk2 inhibitors. Drug Resist Updat 2001; 4(6): 347-67.
[14]
Levin NBM, Pintro VO, de Àvila MB, de Mattos BB, De Azevedo WF Jr. Understanding the Structural Basis for Inhibition of Cyclin-Dependent Kinases. New Pieces in the Molecular Puzzle. Curr Drug Targets 2017; 18(9): 1104-11.
[15]
Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S. The protein kinase complement of the human genome. Science 2002; 298(5600): 1912-34.
[16]
Bettayeb K, Oumata N, Echalier A, et al. CR8, a potent and selective, roscovitine-derived inhibitor of cyclin-dependent kinases. Oncogene 2008; 27(44): 5797-807.
[17]
Idowu MA. Cyclin-dependent kinases as drug targets for cell growth and proliferation disorders. A role for systems biology approach in drug development. Part I-cyclin-dependent kinases as drug targets in cancer. Biotechnol Biotec 2011; 25(4): 2583-6.
[18]
Tanaka S, Tak YS, Araki H. The role of CDK in the initiation step of DNA replication in eukaryotes. Cell division 2007; 2(1): 16.
[19]
Lim S, Kaldis P. Cdks, cyclins and CKIs: Roles beyond cell cycle regulation. Development 2013; 140(15): 3079-93.
[20]
Tsai LH, Harlow E, Meyerson M. Isolation of the human CDK2 gene that encodes the cyclin A-and adenovirus E1Aassociated p33 kinase. Nature 1991; 353(6340): 174-7.
[21]
Eom EM, Cho JK, Lim SO, Byun YJ, Lee DH. Molecular cloning and expression of a small GTP-binding protein of the Rop family from mung bean. Plant Sci 2006; 171(1): 41-51.
[22]
Schulze-Gahmen U, De Bondt HL, Kim SH. High-resolution crystal structures of human cyclin-dependent kinase 2 with and without ATP: bound waters and natural ligand as guides for inhibitor design. J Med Chem 1996; 39(23): 4540-6.
[23]
Davies TG, Pratt DJ, Endicott JA, Johnson LN, Noble ME. Structure based design of cyclin-dependent kinase inhibitors. Pharmacol Ther 2002; 93(2-3): 125-33.
[24]
Sherr CJ. The Pezcoller Lecture: Cancer Cell Cycles Revisited. Cancer Res 2000; 60(14): 3689-95.
[25]
Noble MEM, Endicott JA. Chemical inhibitors of cyclindependent kinases: insights into design from X-ray crystallographic studies. Pharmacol Ther 1999; 82(2-3): 269-78.
[26]
Malumbres M, Barbacid M. Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer 2009; 9(3): 153-66.
[27]
Du J, Widlund HR, Horstmann MA, et al. Critical role of CDK2 for melanoma growth linked to its melanocyte-specific transcriptional regulation by MITF. Cancer Cell 2004; 6(6): 565-76.
[28]
Peyressatre M, Prével C, Pellerano M, Morris M. Targeting cyclin-dependent kinases in human cancers: From small molecules to peptide inhibitors. Cancers 2015; 7(1): 179-237.
[29]
Lowe SW, Cepero E, Evan G. Intrinsic tumour suppression. Nature 2004; 432(7015): 307-15.
[30]
Ahmed D, Sharma M. Cyclin-dependent kinase 5/p35/p39: a novel and imminent therapeutic target for diabetes mellitus. Int J Endocrinol 2011; 2011: 530274.
[31]
Kim JH, Kang MJ, Park CU, Kwak HJ, Hwang Y, Koh GY. Amplified CDK2 and cdc2 activities in primary colorectal carcinoma. Cancer 1999; 85(3): 546-53.
[32]
Yamamoto H, Monden T, Ikeda K, et al. Coexpression of cdk2/cdc2 and retinoblastoma gene products in colorectal cancer. Br J Cancer 1995; 71(6): 1231-6.
[33]
Dobashi Y, Shoji M, Jiang SX, Kobayashi M, Kawakubo Y, Kameya T. Active cyclin a-CDK2 complex, a possible critical factor for cell proliferation in human primary lung carcinomas. Am J Pathol 1998; 153(3): 963-72.
[34]
Lapenna S, Giordano A. Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov 2009; 8(7): 547-66.
[35]
Kuilman T, Michaloglou C, Mooi WJ, Peeper DS. The essence of senescence. Genes Dev 2010; 24(22): 2463-79.
[36]
Salama R, Sadaie M, Hoare M, Narita M. Cellular senescence and its effector programs. Genes Dev 2014; 28(2): 99-114.
[37]
Gire V, Dulić V. Senescence from G2 arrest, revisited. Cell Cycle 2015; 14(3): 297-304.
[38]
O’Connor MJ. Targeting the DNA Damage Response in Cancer. Mol Cell 2015; 60(4): 547-60.
[39]
Bartek J, Lukas C, Lukas J. Checking on DNA damage in S phase. Nat Rev Mol Cell Biol 2004; 5(10): 792-804.
[40]
Macheret M, Halazonetis TD. DNA replication stress as a hallmark of cancer. Annu Rev Pathol Mech Dis 2015; 10: 425-48.
[41]
Müllers E, Silva Cascales H, Burdova K, Macurek L, Lindqvist A. Residual Cdk1/2 activity after DNA damage promotes senescence. Aging Cell 2017; 16(3): 575-84.
[42]
Zhang C, Wang F, Xie Z, et al. Dysregulation of YAP by the Hippo pathway is involved in intervertebral disc degeneration, cell contact inhibition, and cell senescence. Oncotarget 2017; 9(2): 2175-92.
[43]
Zalzali H, Nasr B, Harajly M, et al. Cell cycle and senescence CDK2 transcriptional repression is an essential effector in p53-dependent cellular Senescence— implications for therapeutic intervention. Mol Cancer Res 2015; 13(1): 29-40.
[44]
Collado M, Serrano M. Senescence in tumours: evidence from mice and humans. Nat Rev Cancer 2010; 10(1): 51-7.
[45]
Campisi J, d’Adda di Fagagna F. Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol 2007; 8(9): 729-40.
[46]
Riggelen VJ, Felsher DW. Myc and a Cdk2 senescence switch. Nat Cell Biol 2010; 12(1): 7-9.
[47]
Campaner S, Doni M, Verrecchia A, Fagà G, Bianchi L, Amati B. Myc, Cdk2 and cellular senescence: Old players, new game. Cell Cycle 2010; 9(18): 3679-85.
[48]
Hydbring P, Larsson LG. Tipping the Balance: Cdk2 Enables Myc to Suppress Senescence. Cancer Res 2010; 70(17): 6687-91.
[49]
Zhuang D, Mannava S, Grachtchouk V, et al. C-MYC overexpression is required for continuous suppression of oncogene-induced senescence in melanoma cells. Oncogene 2008; 27(53): 6623-34.
[50]
Wu CH, Van Riggelen J, Yetil A, Fan AC, Bachireddy P, Felsher DW. Cellular senescence is an important mechanism of tumor regression upon c-Myc inactivation. Proc Natl Acad Sci USA 2007; 104(32): 13028-33.
[51]
Beauséjour CM, Krtolica A, Galimi F, et al. Reversal of human cellular senescence: roles of the p53 and p16 pathways. EMBO J 2003; 22: 4212-22.
[52]
Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 1997; 88: 593-602.
[53]
Zhu J, Woods D, McMahon M, Bishop JM. Senescence of human fibroblasts induced by oncogenic Raf. Genes Dev 1998; 12: 2997-3007.
[54]
Campaner S, Doni M, Hydbring P, et al. Cdk2 suppresses cellular senescence induced by the c-myc oncogene. Nat Cell Biol 2010; 12(1): 54-9.
[55]
Schmitt CA. Cellular senescence and cancer treatment. Biochim Biophys Acta 2006; 1775: 5-20.
[56]
Schmitt CA, et al. A senescence program controlled by p53 and p16INK4a contributes to the outcome of cancer therapy. Cell 2002; 109: 335-46.
[57]
Goga A, Yang D, Tward AD, Morgan DO, Bishop JM. Inhibition of CDK1 as a potential therapy for tumors over-expressing MYC. Nat Med 2007; 13: 820-7.
[58]
Hydbring P, Bahram F, Su Y, Tronnersjo S, Hogstrand K, et al. Phosphorylation by Cdk2 is required for Myc to repress Ras‐ induced senescence in cotransformation. Proc Natl Acad Sci USA 2010; 107: 58-63.
[59]
Fadel V, Bettendorff P, Herrmann T, et al. Automated NMR structure determination and disulfide bond identification of the myotoxin crotamine from Crotalus durissus terrificus. Toxicon 2005; 46(7): 759-67.
[60]
Canduri F, de Azevedo WF. Protein crystallography in drug discovery. Curr Drug Targets 2008; 9(12): 1048-53.
[61]
Berman HM, Westbrook J, Feng Z, et al. The Protein Data Bank. Nucleic Acids Res 2000; 28(1): 235-42.
[62]
Berman HM, Battistuz T, Bhat TN, et al. The Protein Data Bank. Acta Crystallogr D Biol Crystallogr 2002; 58(Pt 6 No 1): 899-907.
[63]
Westbrook J, Feng Z, Chen L, Yang H, Berman HM. The Protein Data Bank and structural genomics. Nucleic Acids Res 2003; 31(1): 489-91.
[64]
Liu T, Lin Y, Wen X, Jorissen RN, Gilson MK. BindingDB: a web-accessible database of experimentally determined protein–ligand binding affinities. Nucleic Acids Res 2007; 35(Database issue): D198-201.
[65]
Gilson MK, Liu T, Baitaluk M, et al. BindingDB in 2015: A public database for medicinal chemistry, computational chemistry and systems pharmacology. Nucleic Acids Res 2015; 44(D1): D1045-53.
[66]
Benson ML, Smith RD, Khazanov NA, et al. Binding MOAD, a high-quality protein-ligand database. Nucleic Acids Res 2008; 36(Database issue): D674-8.
[67]
Ahmed A, Smith RD, Clark JJ, Dunbar Jr JB, Carlson HA. Recent improvements to Binding MOAD: a resource for protein–ligand binding affinities and structures. Nucleic Acids Res 2015; 43(Database issue): D465-9.
[68]
Wang R, Fang X, Lu Y, Wang S. The PDBbind database: collection of binding affinities for protein-ligand complexes with known three-dimensional structures. J Med Chem 2004; 47(12): 2977-80.
[69]
Liu Z, Li Y, Han L, et al. PDB-wide collection of binding data: current status of the PDBbind database. Bioinformatics 2015; 31(3): 405-12.
[70]
Schulze-Gahmen U, Brandsen J, Jones HD, et al. Multiple modes of ligand recognition: crystal structures of cyclin-dependent protein kinase 2 in complex with ATP and two inhibitors, olomoucine and isopentenyladenine. Proteins 1995; 22(4): 378-91.
[71]
Xavier MM, Heck GS, de Avila MB, et al. SAnDReS a computational tool for statistical analysis of docking results and development of scoring functions. Comb Chem High Throughput Screen 2016; 19(10): 801-12.
[72]
Wallace AC, Laskowski RA, Thornton JM. LIGPLOT: a program to generate schematic diagrams of protein-ligand interactions. Protein Eng 1995; 8(2): 127-34.
[73]
Laskowski RA, Swindells MB. LigPlot+: multiple ligand-protein interaction diagrams for drug discovery. J Chem Inf Model 2011; 51(10): 2778-86.
[74]
De Azevedo WF Jr, Leclerc S, Meijer L, et al. Inhibition of cyclin-dependent kinases by purine analogues: crystal structure of human cdk2 complexed with roscovitine. Eur J Biochem 1997; 243(1-2): 518-26.
[75]
De Azevedo WF Jr, Mueller-Dieckmann HJ, Schulze-Gahmen U, et al. Structural basis for specificity and potency of a flavonoid inhibitor of human CDK2, a cell cycle kinase. Proc Natl Acad Sci USA 1996; 93(7): 2735-40.
[76]
Canduri F, Teodoro LG, Fadel V, et al. Structure of human uropepsin at 2.45 A resolution. Acta Crystallogr D Biol Crystallogr 2001; 57(Pt 11): 1560-70.
[77]
De Azevedo WF Jr, Canduri F, da Silveira NJ. Structural basis for inhibition of cyclin-dependent kinase 9 by flavopiridol. Biochem Biophys Res Commun 2002; 293(1): 566-71.
[78]
De Azevedo WF Jr, Gaspar RT, Canduri F, Camera JC Jr, da Silveira NJF. Molecular model of cyclin-dependent kinase 5 complexed with roscovitine. Biochem Biophys Res Commun 2002; 297(5): 1154-8.
[79]
De Bondt HL, Rosenblatt J, Jancarik J, et al. Crystal structure of cyclin-dependent kinase 2. Nature 1993; 363(6430): 595-602.
[80]
Thomsen R, Christensen MH. MolDock: a new technique for high-accuracy molecular docking. J Med Chem 2006; 49(11): 3315-21.
[81]
Azevedo WF, Leclerc S, Meijer L, et al. Inhibition of cyclin‐dependent kinases by purine analogues. FEBS J 1997; 243(1‐2): 518-26.
[82]
Meijer L, Raymond E. Roscovitine and other purines as kinase inhibitors. From starfish oocytes to clinical trials. Acc Chem Res 2003; 36(6): 417-25.
[83]
Canduri F, Azevedo J. Structural basis for interaction of inhibitors with cyclin-dependent kinase 2. Curr Comput Aided Drug Des 2005; 1(1): 53-64.
[84]
Levin NM, Pintro VO, de Ávila MB, de Mattos BB, de Azevedo WF Jr. (2017). Understanding the structural basis for inhibition of cyclin-dependent kinases. New pieces in the molecular puzzle. Curr Drug Targets 2017; 18(9): 1104-11.
[85]
Paparidis NF, Durvale MC, Canduri F. The emerging picture of CDK9/P-TEFb: more than 20 years of advances since PITALRE. Mol Biosyst 2017; 13(2): 246-76.
[86]
Dos Santos PNF, Canduri F. The Emerging Picture of CDK11: Genetic, Functional and Medicinal Aspects. Curr Med Chem 2018; 25(8): 880-8.
[87]
Wu SY, McNae I, Kontopidis G, et al. Discovery of a novel family of CDK inhibitors with the program LIDAEUS: structural basis for ligand-induced disordering of the activation loop. Structure 2003; 11(4): 399-410.
[88]
Fischmann TO, Hruza A, Duca JS, et al. Structure-guided discovery of cyclin-dependent kinase inhibitors. Biopolymers 2008; 89(5): 372-9.
[89]
Anderson DR, Meyers MJ, Kurumbail RG, et al. Benzothiophene inhibitors of MK2. Part 2: improvements in kinase selectivity and cell potency. Bioorg Med Chem Lett 2009; 19(16): 4882-4.
[90]
Anderson M, Beattie JF, Breault GA, et al. Imidazo [1,2-a]pyridines: a potent and selective class of cyclin-dependent kinase inhibitors identified through structure-based hybridisation. Bioorg Med Chem Lett 2003; 13(18): 3021-6.
[91]
Byth KF, Cooper N, Culshaw JD, et al. Imidazo [1,2-b]pyridazines: a potent and selective class of cyclin-dependent kinase inhibitors. Bioorg Med Chem Lett 2004; 14(9): 2249-52.
[92]
Yue EW, DiMeo SV, Higley CA, et al. Synthesis and evaluation of indenopyrazoles as cyclin-dependent kinase inhibitors. Part 4: Heterocycles at C3. Bioorg Med Chem Lett 2004; 14(2): 343-6.
[93]
Anderson M, Andrews DM, Barker AJ, et al. Imidazoles: SAR and development of a potent class of cyclin-dependent kinase inhibitors. Bioorg Med Chem Lett 2008; 18(20): 5487-92.
[94]
Heathcote DA, Patel H, Kroll SH, et al. A novel pyrazolo [1,5-a]pyrimidine is a potent inhibitor of cyclin-dependent protein kinases 1, 2, and 9, which demonstrates antitumor effects in human tumor xenografts following oral administration. J Med Chem 2010; 53(24): 8509-22.
[95]
Lücking U, Jautelat R, Krüger M, et al. The lab oddity prevails: discovery of pan-CDK inhibitor (R)-S-cyclopropyl-S-(4-[4-[(1R,2R)-2-hydroxy-1-methylpropyl]oxy-5-(trifluoromethyl)pyrimidin-2-yl]aminophenyl)sulfoximide (BAY 1000394) for the treatment of cancer. ChemMedChem 2013; 8(7): 1067-85.

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy