Structure-based drug design: Synthesis and biological evaluation of quinazolin-4-amine derivatives as selective Aurora A kinase inhibitors.

Abstract

Aurora kinases play critical roles in the regulation of the cell cycle and mitotic spindle assembly. Aurora A kinase, a member of the Aurora protein family, is frequently highly expressed in tumors, and selective Aurora A inhibition serves as a significant component of anticancer therapy. However, designing highly selective Aurora A inhibitors is difficult because Aurora A and B share high homology and differ only by three residues in their ATP-binding pockets. Through structure-based drug design, we designed and synthesized a series of novel quinazolin-4-amine derivatives. These derivatives act as selective Aurora A kinase inhibitors by exploiting the structural differences between Aurora A and B. The selectivities of most compounds were improved (the best up to >757-fold) when comparing with the lead compound (3-fold). In vitro biochemical and cellular assays revealed that compound 6 potently inhibited Aurora A kinase and most human tumor cells. Furthermore, compound 6 effectively suppressed carcinoma, such as triple-negative breast cancers (TNBC) in an animal model. Therefore, compound 6 might serve as a promising anticancer drug. Moreover, through molecular dynamic (MD) analysis, we have identified that a salt bridge formed in Aurora B is key contributor for the isoform selectivity of the inhibitor. This salt bridge has not been previously detected in the reported crystal structure of Aurora B. These results might provide a crucial basis for the further development of highly potent inhibitors with high selectivity for Aurora A.

• Authors: Liang Long, Yong-Heng Wang, Jun-Xiao Zhuo, Zheng-Chao Tu, Ruibo Wu, Min Yan, Quentin Liu, Gui Lu
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 157 Pg. 1361-1375 (Sep 05 2018) ISSN: 1768-3254 [Electronic] France
• PMID: 30196060 (Publication Type: Journal Article)
• Copyright: Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Chemical References

• Protein Kinase Inhibitors
• Quinazolines
• quinazolin-4-amine
• AURKA protein, human
• Aurora Kinase A

Topics

• Aurora Kinase A (antagonists & inhibitors, metabolism)
• Dose-Response Relationship, Drug
• Drug Design
• Humans
• Models, Molecular
• Molecular Structure
• Protein Kinase Inhibitors (chemical synthesis, chemistry, pharmacology)
• Quinazolines (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship