Identification, SAR Studies, and X‐ray Co‐crystallographic Analysis of a Novel Furanopyrimidine Aurora Kinase A Inhibitor

Abstract

Herein we reveal a simple method for the identification of novel Aurora kinase A inhibitors through substructure searching of an in-house compound library to select compounds for testing. A hydrazone fragment conferring Aurora kinase activity and heterocyclic rings most frequently reported in kinase inhibitors were used as substructure queries to filter the in-house compound library collection prior to testing. Five new series of Aurora kinase inhibitors were identified through this strategy, with IC(50) values ranging from approximately 300 nM to approximately 15 microM, by testing only 133 compounds from a database of approximately 125,000 compounds. Structure-activity relationship studies and X-ray co-crystallographic analysis of the most potent compound, a furanopyrimidine derivative with an IC(50) value of 309 nM toward Aurora kinase A, were carried out. The knowledge gained through these studies could help in the future design of potent Aurora kinase inhibitors.

BPR1K653, a Novel Aurora Kinase Inhibitor, Exhibits Potent Anti-Proliferative Activity in MDR1 (P-gp170)-Mediated Multidrug-Resistant Cancer Cells

“…In this study, we have developed a novel pan-Aurora kinase inhibitor BPR1K653 and further demonstrated its efficacy in targeting various types of cancers in vitro . Our pervious x-ray co-crystallography studies had demonstrated the physical interactions between the precursor compound of BPR1K653 and Aurora kinases [42], and the current in vitro kinase inhibition study has confirmed the target specificity of BPR1K653. Consistent with the molecular changes observed in cells treated with Aurora-B kinase specific siRNA oligos and with different pan-Aurora kinase inhibitors such as VX680 and SNS-314 [14], [43], [44], BPR1K653 treatment also induces endo-replication of cells and reduces amount of phosphorylated Histone H3 present in cells.…”

Aurora kinase inhibitors reveal mechanisms of HURP in nucleation of centrosomal and kinetochore microtubules

“…We have reported a lead compound with a furanopyrimidine core capable of inhibiting Aurora kinase activity (20,21). Using this structure as a scaffold, we synthesized (Fig.…”

Identification of ligand efficient, fragment-like hits from an HTS library: structure-based virtual screening and docking investigations of 2H- and 3H-pyrazolo tautomers for Aurora kinase A selectivity

“…Analysis of these set of compounds revealed that some had a hydrazone functional group embedded in them. We have already reported several compounds bearing hydrazone fragments as Aurora kinase inhibitors, including those with pyrazole rings [14,25]. The pyrazole-hydrazones reported in ref 25 could not be further developed due to their chemical instability.…”

“…The other submicromolar inhibitor 7, with an IC 50 of 852 nM, was identified by sub-structure searching of the database for the hit 3 identified in Libdock VS, and has a tricyclic pyrazole core. It should be noted that none of the hits 3-9 were tested/identified during our previous HTS database screening campaign [14,27].…”

“…1) [14]. Further optimization of hit 1 by structure-based drug design led to the development of potent Aurora kinase inhibitor lead 2 (Aurora A IC 50 = 43 nM, LE = 0.25) [15].…”