VX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo

Abstract

The Aurora kinases are essential for the regulation of chromosome segregation and cytokinesis during mitosis. Aberrant expression and activity of these kinases occur in a wide range of human tumors, and lead to aneuploidy and tumorigenesis. Here we report the discovery of a highly potent and selective small-molecule inhibitor of Aurora kinases, VX-680, that blocks cell-cycle progression and induces apoptosis in a diverse range of human tumor types. This compound causes profound inhibition of tumor growth in a variety of in vivo xenograft models, leading to regression of leukemia, colon and pancreatic tumors at well-tolerated doses. Our data indicate that Aurora kinase inhibition provides a new approach for the treatment of multiple human malignancies.

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

“…The Aurora kinases represent one such class of molecular targets that are essential for progression through mitosis, and small molecule inhibitors of these kinases possess broad antitumor efficacy that has not yet been shown to discriminate on a cancer genetic basis. 7,11 Although it has been demonstrated that cancer cells deficient in p53 show accelerated polyploidization when treated with VX-680, 23 this does not appear to represent genetic susceptibility per se as cells harboring wild-type p53 are also subject to polyploidization-mediated cell death, though perhaps with delayed kinetics. Our data provide genetic evidence to indicate that the Aurora kinase inhibitor, AZD1152, which is currently undergoing clinical evaluation and potentially of another clinical compound, VX-680, may be relatively ineffective in tumor cells that overexpress MDR1 or BCRP.…”

“…ethyl Dihydrogen Phosphate) 10 and VX-680/MK-0457 (cyclopropane carboxylic acid {4-[4-(4-methyl-piperazin-1-yl)-6-(5-methyl-2H-pyrazol-3-ylamino)-pyrimidin-2-ylsulphanyl]-phenyl}-amide) 38 have been disclosed. These compounds were synthesized at Abbott Laboratories for comparative purposes.…”

“…Several small-molecule inhibitors have been developed including Hesperadin, ZM447439, VX-680/MK0457, AZD1152 and MLN8054. [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.…”

Repression of cancer cell senescence by PKCι

“…The aurora kinases are known to have a central role in the control of mitosis (Barr and Gergely, 2007). The pan-aurora kinase inhibitor VX-680 was used for these experiments (Harrington et al, 2004). VX-680 on its own caused an increase in the number of senescent MCF7 cells and also enhanced the effects of PKCi depletion on senescence induction (Figure 6a).…”

An integrated pharmacokinetic–pharmacodynamic model for an Aurora kinase inhibitor

“…Biomarkers identified for AK-A and AK-B are phosphorylated Aurora kinase A and phosphorylated histone H3, respectively [23,24,25]. We will make use of these relationships.…”