Sarvagalla Sailu, Coumar Mohane Selvaraj
Centre for Bioinformatics, School of Life Sciences, Pondicherry University, Kalapet, Puducherry 605014, India.
Curr Cancer Drug Targets. 2015;15(5):375-93. doi: 10.2174/1568009615666150421110401.
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.
极光激酶A、B和C是有丝分裂的关键调节因子，在许多人类癌症中过度表达，这使它们成为癌症化疗的理想药物靶点。目前，有十多种极光激酶抑制剂正处于临床开发的不同阶段。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）是泛选择性的（亚型非选择性），只有少数是极光A（MLN8054、MLN8237、VX-689/MK5108和ENMD 2076）和极光B（AZD1152和GSK1070916）亚型选择性的。尽管在过去十年中进行了深入研究，但尚无极光激酶抑制剂上市。最近的证据表明，亚型选择性极光激酶A抑制剂可能比泛选择性极光抑制剂更具优势，因为它可以避免极光B介导的中性粒细胞减少。然而，由于亚型之间活性位点相似，亚型选择性极光激酶A抑制剂的设计极具挑战性。对与极光激酶抑制剂设计相关的结构生物学和计算方面进行了分析，发现开发亚型选择性抑制剂的一种可能方法是针对蛋白质溶剂暴露区域附近的极光A特异性残基（Leu215、Thr217和Arg220）或极光B特异性残基（Arg159、Glu161和Lys164）。特别是，设计亚型选择性极光A抑制剂的一种有用策略可能是像MLN8054那样针对Thr217残基。对亚型选择性极光抑制剂进行进一步的临床前和临床研究可能有助于将它们推向市场用于癌症治疗。
