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摘要
多靶点药物可以依次与多个靶点相互作用,即使活性相对适度,也能对包括癌症在内的多种复杂疾病产生协同作用和更有效的治疗。组蛋白脱乙酰酶(HDAC)抑制剂是低分子量的小化合物,可增加组蛋白和非组蛋白的乙酰化,改变基因表达,从而影响血管生成、转移和细胞凋亡等过程。 HDAC 抑制剂影响多种细胞通路,从而产生不良问题,导致治疗耐药性,并且它们的药代动力学特性较差。设计基于 HDAC 的双/多靶点抑制剂是克服不良反应、耐药性和提高控制癌症有效性的重要策略。设计多靶点HDAC抑制剂的靶点组合选择一般是在系统高通量筛选(HTS)、网络药理学分析方法的基础上完成的。使用理性或计算方法执行药效团针对单个目标的识别。鉴定的药效团可以与可裂解或不可裂解的接头合并、融合或连接,以保留与原始靶标的相互作用,同时与其他靶标兼容。本综述的目的是阐明潜在靶标的设计策略、生物活性,以及作为潜在抗癌剂的双重/多靶点 HDAC 抑制剂的最新发展。本综述阐述了潜在靶标的设计策略以及生物活性,以及双/多靶点 HDAC 抑制剂作为潜在抗癌剂的最新发展。基于 HDAC 的双/多靶点抑制剂的开发对于克服副作用、耐药性和有效的癌症控制非常重要。
关键词: 组蛋白去乙酰酶,HDAC抑制剂,抗癌,双/多靶点,设计策略,计算方法,最新进展。
[http://dx.doi.org/10.1021/acs.jmedchem.1c00683] [PMID: 34313432]
[http://dx.doi.org/10.1021/acs.jcim.6b00491] [PMID: 28166637]
[http://dx.doi.org/10.1021/acs.jmedchem.8b00760] [PMID: 30035545]
[http://dx.doi.org/10.1021/ci500021v] [PMID: 24611712]
[http://dx.doi.org/10.1517/13543784.2014.857401] [PMID: 24205827]
[http://dx.doi.org/10.1186/s40169-017-0181-2] [PMID: 29340951]
[http://dx.doi.org/10.1371/journal.pone.0165737] [PMID: 27828998]
[http://dx.doi.org/10.1039/b703830p] [PMID: 18568166]
[http://dx.doi.org/10.1038/scientificamerican0281-52] [PMID: 7209486]
[http://dx.doi.org/10.1016/S0968-0004(00)01718-7] [PMID: 11116189]
[http://dx.doi.org/10.2217/fon-2020-0385] [PMID: 32815411]
[http://dx.doi.org/10.1038/nature10728] [PMID: 22230954]
[http://dx.doi.org/10.1016/S0898-6568(00)00131-5] [PMID: 11152955]
[http://dx.doi.org/10.1074/jbc.M111871200] [PMID: 11948178]
[http://dx.doi.org/10.1038/43710] [PMID: 10490031]
[http://dx.doi.org/10.1101/gad.9.23.2888] [PMID: 7498786]
[http://dx.doi.org/10.1007/s12253-019-00663-8] [PMID: 31055775]
[http://dx.doi.org/10.2174/0929867311320140006] [PMID: 23409715]
[http://dx.doi.org/10.3390/molecules20033898] [PMID: 25738536]
[http://dx.doi.org/10.1517/13543776.17.7.745]
[http://dx.doi.org/10.1002/minf.200900014] [PMID: 27463196]
[http://dx.doi.org/10.1002/cmdc.201300433] [PMID: 24375963]
[http://dx.doi.org/10.1002/cmdc.200900500] [PMID: 20157916]
[http://dx.doi.org/10.2174/1568009617666170630124643] [PMID: 28669336]
[http://dx.doi.org/10.2174/1568009617666170109150134] [PMID: 28067178]
[http://dx.doi.org/10.2174/1573409914666180502113135] [PMID: 29732991]
[http://dx.doi.org/10.1016/j.molstruc.2021.130590]
[http://dx.doi.org/10.1016/j.ejmech.2020.112831] [PMID: 32961382]
[http://dx.doi.org/10.1042/BJ20070779] [PMID: 17868033]
[http://dx.doi.org/10.1016/j.ejmech.2020.112844] [PMID: 33143937]
[http://dx.doi.org/10.1371/journal.pone.0053100] [PMID: 23372654]
[http://dx.doi.org/10.2165/11315680-000000000-00000] [PMID: 19747008]
[http://dx.doi.org/10.1021/acs.jmedchem.6b00908] [PMID: 27606546]
[http://dx.doi.org/10.1016/j.ejmech.2017.05.016] [PMID: 28494256]
[http://dx.doi.org/10.1016/j.ejmech.2017.10.040] [PMID: 29133060]
[http://dx.doi.org/10.1016/j.ejmech.2020.112904] [PMID: 33077264]
[http://dx.doi.org/10.3389/fonc.2018.00092] [PMID: 29651407]
[http://dx.doi.org/10.3390/ijms21218198] [PMID: 33147762]
[http://dx.doi.org/10.2147/BTT.S29965] [PMID: 23459471]
[http://dx.doi.org/10.1021/acs.jmedchem.0c00491] [PMID: 32320239]
[http://dx.doi.org/10.1021/ml1002162] [PMID: 21499541]
[http://dx.doi.org/10.1021/jm400179b] [PMID: 23570542]
[http://dx.doi.org/10.1073/pnas.0709279105] [PMID: 18550844]
[http://dx.doi.org/10.1021/acs.jmedchem.7b00398] [PMID: 28845983]
[http://dx.doi.org/10.1016/j.bmc.2010.06.042] [PMID: 20620068]
[http://dx.doi.org/10.1016/S1470-2045(04)01509-8] [PMID: 15231248]
[http://dx.doi.org/10.1016/j.ctrv.2004.04.004] [PMID: 15325034]
[http://dx.doi.org/10.1111/j.1476-5381.2011.01383.x] [PMID: 21449912]
[http://dx.doi.org/10.1111/j.1365-2141.2009.07902.x] [PMID: 19793255]
[PMID: 11948134]
[http://dx.doi.org/10.1021/acs.jmedchem.1c00491] [PMID: 34006099]
[http://dx.doi.org/10.1158/0008-5472.CAN-07-5807] [PMID: 18381445]
[http://dx.doi.org/10.1126/science.1059344] [PMID: 11349148]
[http://dx.doi.org/10.2174/156802606777864890] [PMID: 16848743]
[http://dx.doi.org/10.1158/1535-7163.MCT-05-0539] [PMID: 16648549]
[http://dx.doi.org/10.1016/j.bmc.2010.03.078] [PMID: 20452225]
[http://dx.doi.org/10.1073/pnas.1608067113] [PMID: 27799547]
[http://dx.doi.org/10.1158/1535-7163.MCT-11-0433] [PMID: 22072815]
[http://dx.doi.org/10.1021/acs.jmedchem.8b01487] [PMID: 30365892]
[http://dx.doi.org/10.1016/S0162-3109(00)00188-0] [PMID: 10878285]
[http://dx.doi.org/10.1128/AAC.02816-15] [PMID: 27139487]
[http://dx.doi.org/10.1021/jm070864w] [PMID: 18038969]
[http://dx.doi.org/10.1016/j.bmc.2010.06.081] [PMID: 20650640]
[http://dx.doi.org/10.1021/acs.jmedchem.6b00324] [PMID: 27224875]
[http://dx.doi.org/10.1021/acs.jmedchem.7b00467] [PMID: 28885834]
[http://dx.doi.org/10.1021/jm701079h] [PMID: 17941625]
[http://dx.doi.org/10.1038/bjp.2008.23] [PMID: 18311159]
[http://dx.doi.org/10.3389/fimmu.2016.00109] [PMID: 27066002]
[http://dx.doi.org/10.1021/acs.jmedchem.1c01155] [PMID: 34783558]
[http://dx.doi.org/10.1016/j.tips.2020.04.008] [PMID: 32448557]
[http://dx.doi.org/10.3390/molecules21040466] [PMID: 27070562]
[http://dx.doi.org/10.5582/ddt.2015.01001] [PMID: 26193935]
[http://dx.doi.org/10.1016/j.phrs.2021.105463] [PMID: 33513356]
[http://dx.doi.org/10.1016/j.bcp.2020.114224] [PMID: 32956642]
[http://dx.doi.org/10.1016/j.semcancer.2020.11.005]
[http://dx.doi.org/10.1021/acs.jmedchem.8b00189] [PMID: 30418766]
[PMID: 22843888]
[http://dx.doi.org/10.1038/cddis.2013.330] [PMID: 24052078]
[http://dx.doi.org/10.1158/1078-0432.CCR-12-3909] [PMID: 24520095]
[http://dx.doi.org/10.1186/s12885-015-1967-5] [PMID: 26675484]
[http://dx.doi.org/10.1158/0008-5472.CAN-04-0540] [PMID: 15374977]
[http://dx.doi.org/10.1016/j.bmc.2016.10.006] [PMID: 27769671]
[http://dx.doi.org/10.1016/j.bmc.2012.05.034] [PMID: 22698782]
[http://dx.doi.org/10.1021/jm901453q] [PMID: 20143778]
[http://dx.doi.org/10.1172/JCI24652] [PMID: 16741576]
[http://dx.doi.org/10.1039/C4MD00211C]
[http://dx.doi.org/10.1530/ERC-15-0555] [PMID: 27207700]
[http://dx.doi.org/10.1016/j.bmcl.2015.10.006] [PMID: 26475519]
[http://dx.doi.org/10.1016/j.cclet.2017.01.003]
[http://dx.doi.org/10.1684/bdc.2014.1981] [PMID: 24977453]
[http://dx.doi.org/10.1021/acs.jmedchem.8b00384] [PMID: 29787262]
[http://dx.doi.org/10.1039/D0SC01676D] [PMID: 32953006]
[http://dx.doi.org/10.3892/ijo.2013.2042] [PMID: 23900601]
[http://dx.doi.org/10.1016/j.ygyno.2013.02.008] [PMID: 23403163]
[http://dx.doi.org/10.1016/j.ejmech.2020.112322] [PMID: 32361064]
[http://dx.doi.org/10.1016/j.ejmech.2020.112073] [PMID: 31991336]
[http://dx.doi.org/10.2174/092986708785132933] [PMID: 18691045]
[http://dx.doi.org/10.2174/1874312901206010232] [PMID: 23028408]
[http://dx.doi.org/10.1016/j.exphem.2012.10.012] [PMID: 23111066]
[http://dx.doi.org/10.1016/j.leukres.2012.03.003] [PMID: 22475363]
[http://dx.doi.org/10.1021/acs.jmedchem.6b00157] [PMID: 27541357]
[http://dx.doi.org/10.1016/j.ejmech.2015.03.034] [PMID: 25800646]
[http://dx.doi.org/10.1038/onc.2012.330] [PMID: 22926515]
[http://dx.doi.org/10.1007/s11523-017-0484-7] [PMID: 28299600]
[http://dx.doi.org/10.1016/j.bmcl.2019.04.047] [PMID: 31053508]
[http://dx.doi.org/10.1186/s13046-019-1292-y] [PMID: 31277672]
[http://dx.doi.org/10.3390/molecules25071497] [PMID: 32218358]
[http://dx.doi.org/10.1021/acsmedchemlett.9b00561] [PMID: 32435375]
[http://dx.doi.org/10.1186/s12943-018-0796-y] [PMID: 29455668]
[http://dx.doi.org/10.1021/acsmedchemlett.7b00172] [PMID: 28835797]
[http://dx.doi.org/10.3390/cells8060614] [PMID: 31216761]
[http://dx.doi.org/10.1016/j.bmc.2017.12.041] [PMID: 29317150]
[http://dx.doi.org/10.1021/acs.jmedchem.1c00100] [PMID: 34101463]
[http://dx.doi.org/10.1016/j.ejmech.2021.113790] [PMID: 34454126]
[http://dx.doi.org/10.1016/j.ejmech.2016.11.033] [PMID: 27886544]
[http://dx.doi.org/10.3390/ijms20020383] [PMID: 30658435]
[http://dx.doi.org/10.2147/DDDT.S256756] [PMID: 32848361]
[http://dx.doi.org/10.1016/j.fjps.2017.03.003]
[http://dx.doi.org/10.2174/1570180814666170823161751]
[http://dx.doi.org/10.1016/j.ejmech.2015.03.035] [PMID: 25805446]
[http://dx.doi.org/10.1039/C4RA05508J]
[http://dx.doi.org/10.2174/1570180813666160517163444]
[http://dx.doi.org/10.2174/1570180817999200905092444]
[http://dx.doi.org/10.1021/acs.jmedchem.8b00050] [PMID: 30004697]
[http://dx.doi.org/10.1038/nrm831] [PMID: 12042765]
[http://dx.doi.org/10.1021/jm200799p] [PMID: 22260166]
[http://dx.doi.org/10.1016/j.bmc.2013.09.023] [PMID: 24095018]
[http://dx.doi.org/10.1016/j.bmcl.2013.03.108] [PMID: 23622981]
[http://dx.doi.org/10.1371/journal.pone.0205018] [PMID: 30300374]
[http://dx.doi.org/10.1016/j.canlet.2012.09.018] [PMID: 23032720]
[http://dx.doi.org/10.1016/j.bmcl.2017.08.011] [PMID: 28818449]
[http://dx.doi.org/10.1039/b916715c] [PMID: 19885462]
[http://dx.doi.org/10.1016/j.jinorgbio.2017.09.009] [PMID: 28918353]
[http://dx.doi.org/10.1038/nrm.2016.143] [PMID: 28053347]
[http://dx.doi.org/10.1016/j.cell.2013.03.036] [PMID: 23582323]
[http://dx.doi.org/10.1182/blood-2012-02-412783] [PMID: 22451422]
[http://dx.doi.org/10.1002/anie.201915896] [PMID: 31943585]
[http://dx.doi.org/10.1016/j.bmcl.2016.04.034] [PMID: 27142751]
[http://dx.doi.org/10.1021/acs.jmedchem.9b02178] [PMID: 32153186]
[http://dx.doi.org/10.1016/j.bmcl.2017.07.054] [PMID: 28765013]
[http://dx.doi.org/10.3390/ijms19092560] [PMID: 30158430]
[http://dx.doi.org/10.1038/s41389-021-00331-0] [PMID: 33986242]
[http://dx.doi.org/10.1016/j.ejmech.2018.03.006] [PMID: 29567459]
[http://dx.doi.org/10.1016/j.ejmech.2019.111725] [PMID: 31655430]
[http://dx.doi.org/10.1016/j.bmcl.2018.03.009] [PMID: 29545103]
[http://dx.doi.org/10.1038/nrc1821] [PMID: 16498445]
[http://dx.doi.org/10.1038/nrc745] [PMID: 11990853]
[http://dx.doi.org/10.1016/j.ejmech.2017.02.014] [PMID: 28219048]
[http://dx.doi.org/10.1016/j.phrs.2017.05.002] [PMID: 28501516]
[http://dx.doi.org/10.1016/j.critrevonc.2003.09.001] [PMID: 15157658]
[http://dx.doi.org/10.1016/j.bmc.2012.08.014] [PMID: 22967811]
[http://dx.doi.org/10.1016/j.bmc.2009.02.063] [PMID: 19329328]
[http://dx.doi.org/10.1016/j.bmc.2009.03.017] [PMID: 19339187]
[http://dx.doi.org/10.1080/07391102.2018.1434833] [PMID: 29380672]
[http://dx.doi.org/10.1158/1940-6207.CAPR-11-0166] [PMID: 21778329]
[http://dx.doi.org/10.1016/j.bmc.2016.12.001] [PMID: 28336407]
[http://dx.doi.org/10.4062/biomolther.2012.20.3.256] [PMID: 24130921]
[http://dx.doi.org/10.1007/s10549-006-9459-6] [PMID: 17186358]
[http://dx.doi.org/10.1530/EC-18-0425] [PMID: 30640710]
[PMID: 11585728]
[http://dx.doi.org/10.1158/0008-5472.CAN-10-2458] [PMID: 21245100]
[http://dx.doi.org/10.1002/ijc.24350] [PMID: 19330834]
[http://dx.doi.org/10.1021/jm400467w] [PMID: 23786452]
[http://dx.doi.org/10.1016/j.bmc.2015.11.005] [PMID: 26613635]
[http://dx.doi.org/10.1021/acs.jmedchem.5b00099] [PMID: 25993269]
[http://dx.doi.org/10.1186/s13045-020-00937-8] [PMID: 32723346]
[http://dx.doi.org/10.1021/acsmedchemlett.0c00014] [PMID: 32435414]
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