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

Abstract

BackgroundOver-expression of Aurora kinases promotes the tumorigenesis of cells. The aim of this study was to determine the preclinical profile of a novel pan-Aurora kinase inhibitor, BPR1K653, as a candidate for anti-cancer therapy. Since expression of the drug efflux pump, MDR1, reduces the effectiveness of various chemotherapeutic compounds in human cancers, this study also aimed to determine whether the potency of BPR1K653 could be affected by the expression of MDR1 in cancer cells.Principal FindingsBPR1K653 specifically inhibited the activity of Aurora-A and Aurora-B kinase at low nano-molar concentrations in vitro. Anti-proliferative activity of BPR1K653 was evaluated in various human cancer cell lines. Results of the clonogenic assay showed that BPR1K653 was potent in targeting a variety of cancer cell lines regardless of the tissue origin, p53 status, or expression of MDR1. At the cellular level, BPR1K653 induced endo-replication and subsequent apoptosis in both MDR1-negative and MDR1-positive cancer cells. Importantly, it showed potent activity against the growth of xenograft tumors of the human cervical carcinoma KB and KB-derived MDR1-positive KB-VIN10 cells in nude mice. Finally, BPR1K653 also exhibited favorable pharmacokinetic properties in rats.Conclusions and SignificanceBPR1K653 is a novel potent anti-cancer compound, and its potency is not affected by the expression of the multiple drug resistant protein, MDR1, in cancer cells. Therefore, BPR1K653 is a promising anti-cancer compound that has potential for the management of various malignancies, particularly for patients with MDR1-related drug resistance after prolonged chemotherapeutic treatments.

Functional impact of Aurora A-mediated phosphorylation of HP1γ at serine 83 during cell cycle progression

“…Thus, targeting this pathway would affect P-Ser 83 -HP1γ-mediated cell proliferation, in addition to other downstream Aurora effectors. In fact, Aurora kinase inhibitors have been shown to suppress proliferation of cervical cancer cells and enhance chemosensitivity [40,41], suggesting that targeting Aurora in combination with the HP1-histone methyltransferase pathway may be a beneficial therapy in these patients.…”

CDKN1A-mediated responsiveness ofMLL-AF4-positive acute lymphoblastic leukemia to Aurora kinase-A inhibitors

“…P‐glycoprotein‐encoding multi‐drug resistance gene ( MDR1 ) is detectable in nearly 38% of patients with ALL and confers a high risk of treatment failure. The treatment effect of many Aurora kinase inhibitors can be affected by the expression of MDR1 in cancer cells, but some novel agents are not influenced by MDR1 . We measured the expression of MDR‐1 in 9 ALL cell lines, but detected it only in CCRF‐CEM cells (Supporting Information Fig.…”

Orally Active Aurora A/B Kinase Inhibitor, AM‐005, Suppresses the Growth of Human Colon Carcinoma Cells

“…In this report, we have developed a novel small molecule inhibitor of Aurora kinase inhibitor AM‐005 as an ATP‐competitive compound and further demonstrated its efficacy in human colon carcinoma cell lines. Like AT9283 [Howard et al., ], VX‐680, PHA‐739358 [Carpinelli et al., ], and BPR1K653 [Cheung et al., ], AM‐005 is an Aurora A/B kinase inhibitor, suppressing both Aurora A and B activity. Aurora inhibitor‐induced apoptosis is enhanced in the absence of p53 function [Gizatullin et al., ].…”

“…AT9283 [Howard et al, 2009], VX-680, PHA-739358 [Carpinelli et al, 2007], and BPR1K653 [Cheung et al, 2011], AM-005 is an Aurora A/B kinase inhibitor, suppressing both Aurora A and B activity. Aurora inhibitorinduced apoptosis is enhanced in the absence of p53 function [Gizatullin et al, 2006].…”