Modulation of kinase‐inhibitor interactions by auxiliary protein binding: Crystallography studies on Aurora A interactions with VX‐680 and with TPX2

Zhao, Baoguang; Smallwood, Angela; Yang, Jing; Koretke, Kristin K.; Nurse, Kelvin; Calamari, Amy; Kirkpatrick, Robert B.; Lai, Zhihong

doi:10.1110/ps.036590.108

Cited by 80 publications

(85 citation statements)

References 27 publications

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“…The similarity in effect between Aurora A overexpression and inhibition is consistent with Aurora A requiring a multisubunit complex for its function. Such a multisubunit complex with Aurora A has previously been suggested (32)(33)(34)(35)(36). Disruption of this complex could occur by either inhibition of Aurora A, or by overexpression of Aurora A, the latter serving to sequester necessary components of the complex.…”

Section: Discussionmentioning

confidence: 91%

MLN8054, an Inhibitor of Aurora A Kinase, Induces Senescence in Human Tumor Cells Both In vitro and In vivo

Huck

Zhang

McDonald

et al. 2010

Molecular Cancer Research

105

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Aurora A kinase is a serine/threonine protein kinase responsible for regulating several mitotic processes including centrosome separation, spindle assembly, and chromosome segregation. Small molecule inhibitors of Aurora A kinase are being pursued as novel anticancer agents, some of which have entered clinical trials. Despite the progress in developing these agents, terminal outcomes associated with Aurora A inhibition are not fully understood. Although evidence exists that Aurora A inhibition leads to apoptosis, other therapeutically relevant cell fates have not been reported. Here, we used the small molecule inhibitor MLN8054 to show that inhibition of Aurora A induces tumor cell senescence both in vitro and in vivo. Treatment of human tumor cells grown in culture with MLN8054 showed a number of morphologic and biochemical changes associated with senescence. These include increased staining of senescence-associated β-galactosidase, increased nuclear and cell body size, vacuolated cellular morphology, upregulation/stabilization of p53, p21, and hypophosphorylated pRb. To determine if Aurora A inhibition induces senescence in vivo, HCT-116 xenograft-bearing animals were dosed orally with MLN8054 for 3 weeks. In the MLN8054-treated animals, increased senescence-associated β-galactosidase activity was detected in tissue sections starting on day 15. In addition, DNA and tubulin staining of tumor tissue showed a significant increase in nuclear and cell body area, consistent with a senescent phenotype. Taken together, this data shows that senescence is a terminal outcome of Aurora A inhibition and supports the evaluation of senescence biomarkers in clinic samples. Mol Cancer Res; 8(3); 373-84. ©2010 AACR.

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Section: Discussionmentioning

confidence: 91%

MLN8054, an Inhibitor of Aurora A Kinase, Induces Senescence in Human Tumor Cells Both In vitro and In vivo

Huck

Zhang

McDonald

et al. 2010

Molecular Cancer Research

105

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“…24). The differences are in the portion of the molecule, which confers selectivity in inhibitor/target interactions, based on modeling studies (34,35). The structural changes of ENMD-2076 incorporate a less-derivatized aromatic ring compared with tozasertib (phenyl in ENMD-2076 vs. phenyl-cyclopropanecarboxamide).…”

Section: Discussionmentioning

confidence: 99%

ENMD-2076 Is an Orally Active Kinase Inhibitor with Antiangiogenic and Antiproliferative Mechanisms of Action

Fletcher

Brokx

Denny

et al. 2011

Molecular Cancer Therapeutics

113

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ENMD-2076 is a novel orally active, small molecule kinase inhibitor with a mechanism of action involving several pathways key to tumor growth and survival: angiogenesis, proliferation, and the cell cycle. ENMD-2076 has selective activity against the mitotic kinase Aurora A, as well as kinases involved in angiogenesis (VEGFRs, FGFRs). ENMD-2076 inhibited the growth in vitro of a wide range of human solid tumor and hematopoietic cancer cell lines with IC 50 values ranging from 0.025 to 0.7 mmol/L. ENMD-2076 was also shown to induce regression or complete inhibition of tumor growth in vivo at well-tolerated doses in tumor xenograft models derived from breast, colon, melanoma, leukemia, and multiple myeloma cell lines. Pharmacodynamic experiments in vivo showed that in addition to inhibiting Aurora A, single doses of ENMD-2076 had sustained inhibitory effects on the activation of Flt3 as well as the angiogenic tyrosine kinases, VEGFR2/KDR and FGFR1 and 2. ENMD-2076 was shown to prevent the formation of new blood vessels and regress formed vessels in vivo at doses equivalent to those that gave substantial activity in tumor xenograft models. These results indicate that ENMD-2076 is a well-tolerated, orally active multitarget kinase inhibitor with a unique antiangiogenic/antiproliferative profile and provides strong preclinical support for use as a therapeutic for human cancers. Several phase 1 studies involving ENMD-2076 have been recently completed, and the compound is currently being evaluated in a phase 2 clinical trial in patients with platinumresistant ovarian cancer.

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“…To generate the qualitative hypothesis for Aurora-A and Aurora-B, training set A and B are prepared by selecting 10 and 4 known selective inhibitors based on the receptor binding activity of Aurora-A 1,28,29 and Aurora-B, [30][31][32][33][34] respectively. The 2D format of all molecules were built using MDL-ISIS Draw and converted into 3D using Discovery Studio v2.5 (DS, www.accelrys.com).…”

Section: Methodsmentioning

confidence: 99%

Pharmacophore Modeling and Molecular Dynamics Simulation to Find the Potent Leads for Aurora Kinase B

Sakkiah¹,

Thangapandian²,

Kim³

et al. 2012

Bulletin of the Korean Chemical Society

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Identification of the selective chemical features for Aurora-B inhibitors gained much attraction in drug discovery for the treatment of cancer. Hence to identify the Aurora-B critical features various techniques were utilized such as pharmacophore generation, virtual screening, homology modeling, molecular dynamics, and docking. Top ten hypotheses were generated for Aurora-B and Aurora-A. Among ten hypotheses, HypoB1 and HypoA1 were selected as a best hypothesis for Aurora-B and Aurora-A based on cluster analysis and ranking score, respectively. Test set result revealed that ring aromatic (RA) group in HypoB1 plays an essential role in differentiates Aurora-B from Aurora-A inhibitors. Hence, HypoB1 used as 3D query in virtual screening of databases and the hits were sorted out by applying drug-like properties and molecular docking. The molecular docking result revealed that 15 hits have shown strong hydrogen bond interactions with Ala157, Glu155, and Lys106. Hence, we proposed that HypoB1 might be a reasonable hypothesis to retrieve the structurally diverse and selective leads from various databases to inhibit Aurora-B.

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Modulation of kinase‐inhibitor interactions by auxiliary protein binding: Crystallography studies on Aurora A interactions with VX‐680 and with TPX2

Cited by 80 publications

References 27 publications

MLN8054, an Inhibitor of Aurora A Kinase, Induces Senescence in Human Tumor Cells Both In vitro and In vivo

MLN8054, an Inhibitor of Aurora A Kinase, Induces Senescence in Human Tumor Cells Both In vitro and In vivo

ENMD-2076 Is an Orally Active Kinase Inhibitor with Antiangiogenic and Antiproliferative Mechanisms of Action

Pharmacophore Modeling and Molecular Dynamics Simulation to Find the Potent Leads for Aurora Kinase B

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