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Structure-Based Drug Design of Novel Aurora Kinase A Inhibitors: Structural Basis for Potency and Specificity
- Source :
- Journal of Medicinal Chemistry. 52:1050-1062
- Publication Year :
- 2009
- Publisher :
- American Chemical Society (ACS), 2009.
-
Abstract
- Aurora kinases have emerged as attractive targets for the design of anticancer drugs. Through structure-based virtual screening, novel pyrazole hit 8a was identified as Aurora kinase A inhibitor (IC(50) = 15.1 microM). X-ray cocrystal structure of 8a in complex with Aurora A protein revealed the C-4 position ethyl carboxylate side chain as a possible modification site for improving the potency. On the basis of this insight, bioisosteric replacement of the ester with amide linkage and changing the ethyl substituent to hydrophobic 3-acetamidophenyl ring led to the identification of 12w with a approximately 450-fold improved Aurora kinase A inhibition potency (IC(50) = 33 nM), compared to 8a. Compound 12w showed selective inhibition of Aurora A kinase over Aurora B/C, which might be due to the presence of a unique H-bond interaction between the 3-acetamido group and the Aurora A nonconserved Thr217 residue, which in Aurora B/C is Glu and found to sterically clash with the 3-acetamido group in modeling studies.
- Subjects :
- Stereochemistry
Aurora A kinase
Aurora B kinase
Antineoplastic Agents
Protein Serine-Threonine Kinases
Pyrazole
Crystallography, X-Ray
Substrate Specificity
Inhibitory Concentration 50
Structure-Activity Relationship
chemistry.chemical_compound
Aurora Kinases
Drug Discovery
Aurora Kinase B
Humans
Transferase
Protein Kinase Inhibitors
IC50
Aurora Kinase A
Virtual screening
Molecular Structure
Kinase
Amides
enzymes and coenzymes (carbohydrates)
chemistry
Drug Design
embryonic structures
Molecular Medicine
biological phenomena, cell phenomena, and immunity
Hydrophobic and Hydrophilic Interactions
Subjects
Details
- ISSN :
- 15204804 and 00222623
- Volume :
- 52
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....970481416dd7ba6161a87fb9cce9ef21