The discovery of the potent aurora inhibitor MK-0457 (VX-680)

Bebbington, David; Binch, Hayley; Charrier, Jean-Damien; Everitt, Simon R. L.; Fraysse, Damien; Golec, J. M. C.; Kay, David P.; Knegtel, Ronald M.A.; Mak, Chau; Mazzei, Francesca; Miller, Andrew T.; Mortimore, Michael; O’Donnell, Michael A.; Patel, Sanjay R.; Pierard, Françoise Y. T. M.; Pinder, Joanne L.; Pollard, John R.; Ramaya, Sharn; Robinson, Daniel N.; Rutherford, Alistair; Studley, John; Westcott, James

doi:10.1016/j.bmcl.2009.04.136

Cited by 89 publications

(83 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[53] Structural studies have shown that Gleevec binds to the BCR-Abl Table 1. SAR data for Src and GSK3b [50,51] showing a substantial gain in Src activity if a methyl group is exchanged for a cyclopropyl group at the R 1 position. Table 1: A) The methylpyrazole compound is too small to displace the high-energy hydration sites (two dark blue spheres) at the "rear" of the Src kinase.…”

Section: Abl/c-kitmentioning

confidence: 99%

Understanding Kinase Selectivity Through Energetic Analysis of Binding Site Waters

Robinson¹,

2010

View full text Add to dashboard Cite

Kinases remain an important drug target class within the pharmaceutical industry; however, the rational design of kinase inhibitors is plagued by the complexity of gaining selectivity for a small number of proteins within a family of more than 500 related enzymes. Herein we show how a computational method for identifying the location and thermodynamic properties of water molecules within a protein binding site can yield insight into previously inexplicable selectivity and structure-activity relationships. Four kinase systems (Src family, Abl/c-Kit, Syk/ZAP-70, and CDK2/4) were investigated, and differences in predicted water molecule locations and energetics were able to explain the experimentally observed binding selectivity profiles. The successful predictions across the range of kinases studied here suggest that this methodology could be generally applicable for predicting selectivity profiles in related targets.

show abstract

Section: Abl/c-kitmentioning

confidence: 99%

Understanding Kinase Selectivity Through Energetic Analysis of Binding Site Waters

Robinson¹,

2010

View full text Add to dashboard Cite

show abstract

“…A549 cells were treated with chaetocin, a specific inhibitor of the lysine-specific histone methyltransferase Suv39H1 [41], or VX-680, a known Aurora kinase inhibitor [42], and the changes in Aurora B, H3K9me3 and H3S10ph were examined. Although H3K9me3 and H3S10ph at the pericentromeres were decreased following drug exposure [ Fig.…”

Section: Fk228 Changes Centromeric and Pericentromeric Epigenetic Modmentioning

confidence: 99%

FK228 induces mitotic catastrophe in A549 cells by mistargeting chromosomal passenger complex localization through changing centromeric H3K9 hypoacetylation

Zhang¹,

Zhang²,

Chen³

et al. 2010

ABBS

View full text Add to dashboard Cite

Previous studies have shown that histone deacetylase inhibitors (HDACis) can kill cancer cells. In addition, HDACis can induce mitotic catastrophe in cancer cells due to insufficient localization of chromosomal passenger complex (CPC) to the centromere. However, the mechanisms behind these phenomena remain unclear. In this study, we found that a HDACi, FK228, affected multiple epigenetic modification characteristics of the centromere, including enhanced acetylation of histone H3 lysine 9 (H3K9), decreased trimethylation of H3K9, and decreased phosphorylation of histone H3 serine 10 (H3S10) and centromere protein A (CENP-A). These epigenetic changes implied that H3K9 hyperacetylation inhibits the CPC recruitment, induces impaired centromere assembly and function, and eventually leads to aberrant mitosis. These data suggested that hypoacetylation of histone in the pericentromere is the most important landmark for recruiting CPC and leading to the mitotic catastrophe in HDACiinduced killing of cancer cells.

show abstract

“…36 Unfortunately, the development of MK-0457 was halted for commercial reasons. QTc prolongation 37 or any adverse events was not involved in the closing of the phase 2 study, which confirmed significant activity in patients with T315I. PHA-739358 also has been reported to have strong antiproliferative and proapoptotic activity against BCR-ABL including T315I.…”

Section: Discussionmentioning

confidence: 50%

Activity of the multitargeted kinase inhibitor, AT9283, in imatinib-resistant BCR-ABL–positive leukemic cells

Tanaka

Squires²,

Kimura

et al. 2010

Blood

View full text Add to dashboard Cite

IntroductionPhiladelphia (Ph) chromosome results from a reciprocal translocation between chromosomes 9 and 22 and generates the BCR-ABL chimera protein, the cause of chronic myeloid leukemia (CML) and Ph ϩ acute lymphoid leukemia (ALL). The ABL tyrosine kinase inhibitor (TKI), imatinib mesylate, has dramatically changed the first-line therapy of CML. 1 Most patients with newly diagnosed CML with chronic phase, when treated with imatinib, achieve durable responses. However, emergence of refractory disease and relapse have frequently been reported, particularly in patients with CML with advanced-stage disease and patients with Ph ϩ ALL. 2,3 Among several mechanisms of resistance, point mutations within the ABL kinase domain that interfere with imatinib binding are the most critical cause of imatinib resistance. 4,5 To overcome these imatinib resistance mechanisms, 4 secondgeneration ABL TKIs have been developed: dasatinib, 6 nilotinib, 7 bosutinib 8 and bafetinib (formerly INNO-406). 9,10 Despite promising clinical results from these second-generation ABL TKIs for most patients with imatinib-resistant BCR-ABL ϩ leukemia, the mutation of threonine 315 to isoleucine (T315I) confers resistance to all these TKIs. 11,12 Thus, identification of novel agents for the effective treatment of patients with CML with T315I is an important and challenging task. 13 Aurora kinases A and B are a family of serine/threonine kinases involved in many cellular functions. [14][15][16] Inappropriate expression of these enzymes in certain cancers may result in aneuploidy and carcinogenesis. 17 Consequently, the potential therapeutic value of targeting Aurora kinases has become a focus of anticancer therapy. 14 Recently, we identified an Aurora kinase inhibitor, AT9283 (1-cyclopropyl-3[5-morpholin-4yl methyl-1H-benzomidazol-2-yl]-urea) by way of structure-based optimization of a ligand-efficient pyrazole-benzimidazole fragment. X-ray crystallographic structures were generated with the use of a novel soakable form of Aurora A and were used to drive the optimization toward potent (half-maximal inhibition constant [IC 50 ] Ͻ 3nM) dual Aurora A/B inhibitor. AT9283 that also potently inhibits several kinases, including Janus kinase-2 (JAK2) and JAK3 (1.2 and 1.1nM, respectively), c-ABL (110nM), and ABL/T315I (4nM), is currently under evaluation in phase 1 clinical trials for metastatic solid tumors and hematologic malignancies. 18,19 Here, we report the putative mechanism by which AT9283 binds to BCR-ABL/T315I and its activity against imatinib-resistant BCR-ABL ϩ leukemic cells, including those with the T315I mutation. Methods Reagent and cell linesAT9283 was synthesized by Astex Therapeutics Ltd ( Figure 1A). 18 Human CML cell lines (K562, MEG-01, BV173, KU812, MYL, KT-1, and The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC sectio...

show abstract

The discovery of the potent aurora inhibitor MK-0457 (VX-680)

Cited by 89 publications

References 28 publications

Understanding Kinase Selectivity Through Energetic Analysis of Binding Site Waters

Understanding Kinase Selectivity Through Energetic Analysis of Binding Site Waters

FK228 induces mitotic catastrophe in A549 cells by mistargeting chromosomal passenger complex localization through changing centromeric H3K9 hypoacetylation

Activity of the multitargeted kinase inhibitor, AT9283, in imatinib-resistant BCR-ABL–positive leukemic cells

Contact Info

Product

Resources

About