摘要
极光激酶A、B和C是有丝分裂的重要调节因子,在许多人类肿瘤中都有过度表达,使其作为肿瘤化疗的理想靶点。目前,超过12个极光激酶抑制剂在临床开发的各个阶段。大多数抑制剂(VX-680/mk-0457、PHA-739358、CYC116、sns-314、AMG 900、at-9283、SCH - 1473759、abt-348、pf-03814735、r-763/as-703569、kw-2449和tak-901)是平行选择性(异构体非选择性)和少数极光A(mln8054、MLN8237、vx-689/mk5108和ENMD 2076)和极光B(gsk1070916 和AZD1152)亚型选择性。尽管在过去十年进行了众多的研究工作,还没有极光激酶抑制剂进入到市场。最近的证据表明,泛选择性极光抑制剂其通过避免极光乙介导的中性粒细胞减少,这个亚型选择性极光激酶抑制剂可能具有优势。然而,亚型选择性极光激酶抑制剂的设计是非常具有挑战性的,因为活性位点的异构体之间的相似性。结构生物学和计算方面有关极光激酶抑制剂的设计进行了分析,发现可能意味着开发亚型选择性抑制剂是针对极光A特定的残基(leu215、Thr217和arg220)或极光B特定残基(Arg159、Glu161和lys164),附近的蛋白质的溶剂暴露的区域。特别是,对亚型选择性极光 A抑制剂可以通过针对Thr217残留在mln8054设计案例的一个有用的策略。进一步的临床前和临床研究的亚型选择性极光抑制剂可以帮助它们进入癌症治疗的市场。
关键词: 极光激酶抑制剂,AZD1152,MLN8237,平移选择性,结构生物学,亚型的选择性,VX-680
图形摘要
Current Cancer Drug Targets
Title:Structural Biology Insight for the Design of Sub-type Selective Aurora Kinase Inhibitors
Volume: 15 Issue: 5
Author(s): Sailu Sarvagalla and Mohane Selvaraj Coumar
Affiliation:
关键词: 极光激酶抑制剂,AZD1152,MLN8237,平移选择性,结构生物学,亚型的选择性,VX-680
摘要: Aurora kinase A, B and C, are key regulators of mitosis and are over expressed in many of the human cancers, making them an ideal drug target for cancer chemotherapy. Currently, over a dozen of Aurora kinase inhibitors are in various phases of clinical development. The majority of the inhibitors (VX-680/MK-0457, PHA-739358, CYC116, SNS-314, AMG 900, AT-9283, SCH- 1473759, ABT-348, PF-03814735, R-763/AS-703569, KW-2449 and TAK-901) are pan-selective (isoform non-selective) and few are Aurora A (MLN8054, MLN8237, VX-689/MK5108 and ENMD 2076) and Aurora B (AZD1152 and GSK1070916) sub-type selective. Despite the intensive research efforts in the past decade, no Aurora kinase inhibitor has reached the market. Recent evidence suggests that the sub-type selective Aurora kinase A inhibitor could possess advantages over pan-selective Aurora inhibitors, by avoiding Aurora B mediated neutropenia. However, sub-type selective Aurora kinase A inhibitor design is very challenging due to the similarity in the active site among the isoforms. Structural biology and computational aspects pertaining to the design of Aurora kinase inhibitors were analyzed and found that a possible means to develop sub-type selective inhibitor is by targeting Aurora A specific residues (Leu215, Thr217 and Arg220) or Aurora B specific residues (Arg159, Glu161 and Lys164), near the solvent exposed region of the protein. Particularly, a useful strategy for the design of sub-type selective Aurora A inhibitor could be by targeting Thr217 residue as in the case of MLN8054. Further preclinical and clinical studies with the sub-type selective Aurora inhibitors could help bring them to the market for the treatment of cancer.
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Cite this article as:
Sailu Sarvagalla and Mohane Selvaraj Coumar , Structural Biology Insight for the Design of Sub-type Selective Aurora Kinase Inhibitors, Current Cancer Drug Targets 2015; 15 (5) . https://dx.doi.org/10.2174/1568009615666150421110401
DOI https://dx.doi.org/10.2174/1568009615666150421110401 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
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