Discovery of novel and potent thiazoloquinazolines as selective Aurora A and B kinase inhibitors

J Med Chem. 2006 Feb 9;49(3):955-70. doi: 10.1021/jm050786h.


The synthesis of a novel series of quinazolines substituted at C4 by five-membered ring aminoheterocycles is reported. Their in vitro structure-activity relationships versus Aurora A and B serine-threonine kinases is discussed. Our results demonstrate that quinazolines with a substituted aminothiazole at C4 possess potent Aurora A and B inhibitory activity and excellent selectivity against a panel of various serine-threonine and tyrosine kinases, as exemplified by compound 46. We found also that the position and nature of the substituent on the thiazole play key roles in cellular potency. Compounds with an acetanilide substituent at C5' have the greatest cellular activity. The importance of the C5' position for substitution has been rationalized by ab initio molecular orbital calculations. Results show that the planar conformation with the sulfur of the thiazole next to the quinazoline N-3 is strongly favored over the other possible planar conformation. Compound 46 is a potent suppressor of the expression of phospho-histone H3 in tumor cells in vitro as well as in vivo, where 46, administered as its phosphate prodrug 54, suppresses the expression of phospho-histone H3 in subcutaneously implanted tumors in nude mice.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Aurora Kinase A
  • Aurora Kinases
  • Cell Line, Tumor
  • Histones / antagonists & inhibitors
  • Histones / biosynthesis
  • Humans
  • Mice
  • Mice, Nude
  • Models, Molecular
  • Molecular Structure
  • Neoplasm Transplantation
  • Organophosphates / chemical synthesis*
  • Organophosphates / chemistry
  • Organophosphates / pharmacology
  • Phosphoproteins / antagonists & inhibitors
  • Phosphoproteins / biosynthesis
  • Prodrugs / chemical synthesis
  • Prodrugs / chemistry
  • Prodrugs / pharmacology
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / chemistry
  • Quantum Theory
  • Quinazolines / chemical synthesis*
  • Quinazolines / chemistry
  • Quinazolines / pharmacology
  • Structure-Activity Relationship
  • Thiazoles / chemical synthesis*
  • Thiazoles / chemistry
  • Thiazoles / pharmacology
  • Xenograft Model Antitumor Assays


  • (1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4-yl)methyl dihydrogen phosphate
  • Antineoplastic Agents
  • Histones
  • Organophosphates
  • Phosphoproteins
  • Prodrugs
  • Quinazolines
  • Thiazoles
  • Aurka protein, mouse
  • Aurora Kinase A
  • Aurora Kinases
  • Protein-Serine-Threonine Kinases