Discovery, Synthesis, and in Vivo Activity of a New Class of Pyrazoloquinazolines as Selective Inhibitors of Aurora B Kinase

Abstract

The Aurora kinases have been the subject of considerable interest as targets for the development of new anticancer agents. While evidence suggests inhibition of Aurora B kinase gives rise to the more pronounced antiproliferative phenotype, the most clinically advanced agents reported to date typically inhibit both Aurora A and B. We have discovered a series of pyrazoloquinazolines, some of which show greater than 1000-fold selectivity for Aurora B over Aurora A kinase activity, in recombinant enzyme assays. These compounds have been designed for parenteral administration and achieve high levels of solubility by virtue of their ability to be delivered as readily activated phosphate derivatives. The prodrugs are comprehensively converted to the des-phosphate form in vivo, and the active species have advantageous pharmacokinetic properties and safety pharmacology profiles. The compounds display striking in vivo activity, and compound 5 (AZD1152) has been selected for clinical evaluation and is currently in phase 1 clinical trials.

Identification of genes that confer tumor cell resistance to the Aurora B kinase inhibitor, AZD1152

“…[6][7][8][9] AZD1152 is a novel acetanilide-substituted pyrazole-aminoquinazoline prodrug that is rapidly converted to the active drug, AZD1152 HQPA, in human plasma. 10 AZD1152 HQPA is a highly potent and selective inhibitor of Aurora B (K i of 0.36 nM) compared to Aurora A (K i of 1369 nM) and is inactive against a panel of 50 other kinases. 11 AZD1152 potently inhibits the growth of human colon, lung and hematologic tumor xenografts in immunodeficient mice.…”

Structural studies of B-type Aurora kinase inhibitors using computational methods

“…A series of 48 quinazoline derivatives with their inhibitory activities was retrieved from the literature [24,32] . We have considered only the IC 50 value for the cell-based assay (not an enzyme-based assay), which is the inhibition of histone H3 in SW620 cells.…”

“…The 3D-QSAR models were developed using the Comparative [24,32] . The structures A and B correspond to Figure 1 …”

“…AZD1152 and ZM447439 are both quinazoline derivatives in clinical stages. AZD1152 selectively inhibits Aurora B rather than A or C and resulted from the optimization of a series of 5-acetanilide-3-aminopyrazole (3-pyrazole)-substituted quinazolines [24] . Recently, a new class of 1-acetanilide-4-aminopyrazole-substituted quinazoline has been reported as selective Aurora B inhibitors [25] .…”

“…It has been shown in the literature that these computational techniques can strongly support and aid in the design of novel, more potent inhibitors by revealing the mechanics of the drug-receptor interactions [29][30][31] . To explore the further possibilities of novel drugs, we have developed predictive 3D-QSAR models using quinazoline-based Aurora B inhibitors [24,32] .…”