The Experts below are selected from a list of 2886 Experts worldwide ranked by ideXlab platform
Brian L. Hodous - One of the best experts on this subject based on the ideXlab platform.
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preclinical evaluation of amg 900 a novel potent and highly selective pan Aurora Kinase Inhibitor with activity in taxane resistant tumor cell lines
Cancer Research, 2010Co-Authors: Marc Payton, Tammy L. Bush, Grace Tin-yun Chung, Beth Ziegler, Patrick Eden, Patricia Mcelroy, Sandra Ross, Victor J. Cee, Holly L. Deak, Brian L. HodousAbstract:In mammalian cells, the Aurora Kinases (Aurora-A, -B, and -C) play essential roles in regulating cell division. The expression of Aurora-A and -B is elevated in a variety of human cancers and is associated with high proliferation rates and poor prognosis, making them attractive targets for anticancer therapy. AMG 900 is an orally bioavailable, potent, and highly selective pan-Aurora Kinase Inhibitor that is active in taxane-resistant tumor cell lines. In tumor cells, AMG 900 inhibited autophosphorylation of Aurora-A and -B as well as phosphorylation of histone H3 on Ser(10), a proximal substrate of Aurora-B. The predominant cellular response of tumor cells to AMG 900 treatment was aborted cell division without a prolonged mitotic arrest, which ultimately resulted in cell death. AMG 900 inhibited the proliferation of 26 tumor cell lines, including cell lines resistant to the antimitotic drug paclitaxel and to other Aurora Kinase Inhibitors (AZD1152, MK-0457, and PHA-739358), at low nanomolar concentrations. Furthermore, AMG 900 was active in an AZD1152-resistant HCT116 variant cell line that harbors an Aurora-B mutation (W221L). Oral administration of AMG 900 blocked the phosphorylation of histone H3 in a dose-dependent manner and significantly inhibited the growth of HCT116 tumor xenografts. Importantly, AMG 900 was broadly active in multiple xenograft models, including 3 multidrug-resistant xenograft models, representing 5 tumor types. AMG 900 has entered clinical evaluation in adult patients with advanced cancers and has the potential to treat tumors refractory to anticancer drugs such as the taxanes.
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Preclinical Evaluation of AMG 900, a Novel Potent and Highly Selective Pan-Aurora Kinase Inhibitor with Activity in Taxane-Resistant Tumor Cell Lines
Cancer research, 2010Co-Authors: Marc Payton, Tammy L. Bush, Grace Tin-yun Chung, Beth Ziegler, Patrick Eden, Patricia Mcelroy, Sandra Ross, Victor J. Cee, Holly L. Deak, Brian L. HodousAbstract:Findings illustrate the nature of an Aurora Kinase Inhibitor that is distinct from others being studied in this class, in its being active in tumor cells that are resistant to traditional antimitotic drugs such as taxanes.
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Discovery of a potent, selective, and orally bioavailable pyridinyl-pyrimidine phthalazine Aurora Kinase Inhibitor.
Journal of medicinal chemistry, 2010Co-Authors: Victor J. Cee, Holly L. Deak, Brian L. Hodous, Laurie B. Schenkel, Hanh Nho Nguyen, Philip R. Olivieri, Karina Romero, Annette Bak, Steve BellonAbstract:The discovery of Aurora Kinases as essential regulators of cell division has led to intense interest in identifying small molecule Aurora Kinase Inhibitors for the potential treatment of cancer. A high-throughput screening effort identified pyridinyl-pyrimidine 6a as a moderately potent dual Inhibitor of Aurora Kinases -A and -B. Optimization of this hit resulted in an anthranilamide lead (6j) that possessed improved enzyme and cellular activity and exhibited a high level of Kinase selectivity. However, this anthranilamide and subsequent analogues suffered from a lack of oral bioavailability. Converting the internally hydrogen-bonded six-membered pseudo-ring of the anthranilamide to a phthalazine (8a−b) led to a dramatic improvement in oral bioavailability (38−61%F) while maintaining the potency and selectivity characteristics of the anthranilamide series. In a COLO 205 tumor pharmacodynamic assay measuring phosphorylation of the Aurora-B substrate histone H3 at serine 10 (p-histone H3), oral administrati...
Fei Meng Zheng - One of the best experts on this subject based on the ideXlab platform.
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a novel small molecule Aurora Kinase Inhibitor attenuates breast tumor initiating cells and overcomes drug resistance
Molecular Cancer Therapeutics, 2014Co-Authors: Zijie Long, Fei Meng Zheng, Zhi Jie Hou, Yu Luo, Jiang Long Xia, Xiao Ju Lai, Ji Wei Liu, Xi WangAbstract:Chemoresistance is a major cause of cancer treatment failure. Tumor-initiating cells (TIC) have attracted a considerable amount of attention due to their role in chemoresistance and tumor recurrence. Here, we evaluated the small molecule Aurora Kinase Inhibitor AKI603 as a novel agent against TICs in breast cancer. AKI603 significantly inhibited Aurora-A (AurA) Kinase and induced cell-cycle arrest. In addition, the intragastric administration of AKI603 reduced xenograft tumor growth. Interestingly, we found that breast cancer cells that were resistant to epirubicin expressed a high level of activated AurA and also have a high CD24Low/CD44High TIC population. The inhibition of AurA Kinase by AKI603 abolished the epirubicin-induced enrichment of TICs. Moreover, AKI603 suppressed the capacity of cells to form mammosphere and also suppressed the expression of self-renewal genes (β-catenin, c-Myc, Sox2, and Oct4). Thus, our work suggests the potential clinical use of the small molecule Aurora Kinase Inhibitor AKI603 to overcome drug resistance induced by conventional chemotherapeutics in breast cancer. Mol Cancer Ther; 13(8); 1991–2003. ©2014 AACR .
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A Novel Small Molecule Aurora Kinase Inhibitor Attenuates Breast Tumor–Initiating Cells and Overcomes Drug Resistance
Molecular cancer therapeutics, 2014Co-Authors: Fei Meng Zheng, Zijie Long, Zhi Jie Hou, Yu Luo, Jiang Long Xia, Xiao Ju Lai, Ji Wei Liu, Xi Wang, Muhammad KamranAbstract:Chemoresistance is a major cause of cancer treatment failure. Tumor-initiating cells (TIC) have attracted a considerable amount of attention due to their role in chemoresistance and tumor recurrence. Here, we evaluated the small molecule Aurora Kinase Inhibitor AKI603 as a novel agent against TICs in breast cancer. AKI603 significantly inhibited Aurora-A (AurA) Kinase and induced cell-cycle arrest. In addition, the intragastric administration of AKI603 reduced xenograft tumor growth. Interestingly, we found that breast cancer cells that were resistant to epirubicin expressed a high level of activated AurA and also have a high CD24Low/CD44High TIC population. The inhibition of AurA Kinase by AKI603 abolished the epirubicin-induced enrichment of TICs. Moreover, AKI603 suppressed the capacity of cells to form mammosphere and also suppressed the expression of self-renewal genes (β-catenin, c-Myc, Sox2, and Oct4). Thus, our work suggests the potential clinical use of the small molecule Aurora Kinase Inhibitor AKI603 to overcome drug resistance induced by conventional chemotherapeutics in breast cancer. Mol Cancer Ther; 13(8); 1991–2003. ©2014 AACR .
Victor J. Cee - One of the best experts on this subject based on the ideXlab platform.
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preclinical evaluation of amg 900 a novel potent and highly selective pan Aurora Kinase Inhibitor with activity in taxane resistant tumor cell lines
Cancer Research, 2010Co-Authors: Marc Payton, Tammy L. Bush, Grace Tin-yun Chung, Beth Ziegler, Patrick Eden, Patricia Mcelroy, Sandra Ross, Victor J. Cee, Holly L. Deak, Brian L. HodousAbstract:In mammalian cells, the Aurora Kinases (Aurora-A, -B, and -C) play essential roles in regulating cell division. The expression of Aurora-A and -B is elevated in a variety of human cancers and is associated with high proliferation rates and poor prognosis, making them attractive targets for anticancer therapy. AMG 900 is an orally bioavailable, potent, and highly selective pan-Aurora Kinase Inhibitor that is active in taxane-resistant tumor cell lines. In tumor cells, AMG 900 inhibited autophosphorylation of Aurora-A and -B as well as phosphorylation of histone H3 on Ser(10), a proximal substrate of Aurora-B. The predominant cellular response of tumor cells to AMG 900 treatment was aborted cell division without a prolonged mitotic arrest, which ultimately resulted in cell death. AMG 900 inhibited the proliferation of 26 tumor cell lines, including cell lines resistant to the antimitotic drug paclitaxel and to other Aurora Kinase Inhibitors (AZD1152, MK-0457, and PHA-739358), at low nanomolar concentrations. Furthermore, AMG 900 was active in an AZD1152-resistant HCT116 variant cell line that harbors an Aurora-B mutation (W221L). Oral administration of AMG 900 blocked the phosphorylation of histone H3 in a dose-dependent manner and significantly inhibited the growth of HCT116 tumor xenografts. Importantly, AMG 900 was broadly active in multiple xenograft models, including 3 multidrug-resistant xenograft models, representing 5 tumor types. AMG 900 has entered clinical evaluation in adult patients with advanced cancers and has the potential to treat tumors refractory to anticancer drugs such as the taxanes.
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Preclinical Evaluation of AMG 900, a Novel Potent and Highly Selective Pan-Aurora Kinase Inhibitor with Activity in Taxane-Resistant Tumor Cell Lines
Cancer research, 2010Co-Authors: Marc Payton, Tammy L. Bush, Grace Tin-yun Chung, Beth Ziegler, Patrick Eden, Patricia Mcelroy, Sandra Ross, Victor J. Cee, Holly L. Deak, Brian L. HodousAbstract:Findings illustrate the nature of an Aurora Kinase Inhibitor that is distinct from others being studied in this class, in its being active in tumor cells that are resistant to traditional antimitotic drugs such as taxanes.
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Discovery of a potent, selective, and orally bioavailable pyridinyl-pyrimidine phthalazine Aurora Kinase Inhibitor.
Journal of medicinal chemistry, 2010Co-Authors: Victor J. Cee, Holly L. Deak, Brian L. Hodous, Laurie B. Schenkel, Hanh Nho Nguyen, Philip R. Olivieri, Karina Romero, Annette Bak, Steve BellonAbstract:The discovery of Aurora Kinases as essential regulators of cell division has led to intense interest in identifying small molecule Aurora Kinase Inhibitors for the potential treatment of cancer. A high-throughput screening effort identified pyridinyl-pyrimidine 6a as a moderately potent dual Inhibitor of Aurora Kinases -A and -B. Optimization of this hit resulted in an anthranilamide lead (6j) that possessed improved enzyme and cellular activity and exhibited a high level of Kinase selectivity. However, this anthranilamide and subsequent analogues suffered from a lack of oral bioavailability. Converting the internally hydrogen-bonded six-membered pseudo-ring of the anthranilamide to a phthalazine (8a−b) led to a dramatic improvement in oral bioavailability (38−61%F) while maintaining the potency and selectivity characteristics of the anthranilamide series. In a COLO 205 tumor pharmacodynamic assay measuring phosphorylation of the Aurora-B substrate histone H3 at serine 10 (p-histone H3), oral administrati...
Marc Payton - One of the best experts on this subject based on the ideXlab platform.
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preclinical evaluation of amg 900 a novel potent and highly selective pan Aurora Kinase Inhibitor with activity in taxane resistant tumor cell lines
Cancer Research, 2010Co-Authors: Marc Payton, Tammy L. Bush, Grace Tin-yun Chung, Beth Ziegler, Patrick Eden, Patricia Mcelroy, Sandra Ross, Victor J. Cee, Holly L. Deak, Brian L. HodousAbstract:In mammalian cells, the Aurora Kinases (Aurora-A, -B, and -C) play essential roles in regulating cell division. The expression of Aurora-A and -B is elevated in a variety of human cancers and is associated with high proliferation rates and poor prognosis, making them attractive targets for anticancer therapy. AMG 900 is an orally bioavailable, potent, and highly selective pan-Aurora Kinase Inhibitor that is active in taxane-resistant tumor cell lines. In tumor cells, AMG 900 inhibited autophosphorylation of Aurora-A and -B as well as phosphorylation of histone H3 on Ser(10), a proximal substrate of Aurora-B. The predominant cellular response of tumor cells to AMG 900 treatment was aborted cell division without a prolonged mitotic arrest, which ultimately resulted in cell death. AMG 900 inhibited the proliferation of 26 tumor cell lines, including cell lines resistant to the antimitotic drug paclitaxel and to other Aurora Kinase Inhibitors (AZD1152, MK-0457, and PHA-739358), at low nanomolar concentrations. Furthermore, AMG 900 was active in an AZD1152-resistant HCT116 variant cell line that harbors an Aurora-B mutation (W221L). Oral administration of AMG 900 blocked the phosphorylation of histone H3 in a dose-dependent manner and significantly inhibited the growth of HCT116 tumor xenografts. Importantly, AMG 900 was broadly active in multiple xenograft models, including 3 multidrug-resistant xenograft models, representing 5 tumor types. AMG 900 has entered clinical evaluation in adult patients with advanced cancers and has the potential to treat tumors refractory to anticancer drugs such as the taxanes.
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Preclinical Evaluation of AMG 900, a Novel Potent and Highly Selective Pan-Aurora Kinase Inhibitor with Activity in Taxane-Resistant Tumor Cell Lines
Cancer research, 2010Co-Authors: Marc Payton, Tammy L. Bush, Grace Tin-yun Chung, Beth Ziegler, Patrick Eden, Patricia Mcelroy, Sandra Ross, Victor J. Cee, Holly L. Deak, Brian L. HodousAbstract:Findings illustrate the nature of an Aurora Kinase Inhibitor that is distinct from others being studied in this class, in its being active in tumor cells that are resistant to traditional antimitotic drugs such as taxanes.
Holly L. Deak - One of the best experts on this subject based on the ideXlab platform.
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preclinical evaluation of amg 900 a novel potent and highly selective pan Aurora Kinase Inhibitor with activity in taxane resistant tumor cell lines
Cancer Research, 2010Co-Authors: Marc Payton, Tammy L. Bush, Grace Tin-yun Chung, Beth Ziegler, Patrick Eden, Patricia Mcelroy, Sandra Ross, Victor J. Cee, Holly L. Deak, Brian L. HodousAbstract:In mammalian cells, the Aurora Kinases (Aurora-A, -B, and -C) play essential roles in regulating cell division. The expression of Aurora-A and -B is elevated in a variety of human cancers and is associated with high proliferation rates and poor prognosis, making them attractive targets for anticancer therapy. AMG 900 is an orally bioavailable, potent, and highly selective pan-Aurora Kinase Inhibitor that is active in taxane-resistant tumor cell lines. In tumor cells, AMG 900 inhibited autophosphorylation of Aurora-A and -B as well as phosphorylation of histone H3 on Ser(10), a proximal substrate of Aurora-B. The predominant cellular response of tumor cells to AMG 900 treatment was aborted cell division without a prolonged mitotic arrest, which ultimately resulted in cell death. AMG 900 inhibited the proliferation of 26 tumor cell lines, including cell lines resistant to the antimitotic drug paclitaxel and to other Aurora Kinase Inhibitors (AZD1152, MK-0457, and PHA-739358), at low nanomolar concentrations. Furthermore, AMG 900 was active in an AZD1152-resistant HCT116 variant cell line that harbors an Aurora-B mutation (W221L). Oral administration of AMG 900 blocked the phosphorylation of histone H3 in a dose-dependent manner and significantly inhibited the growth of HCT116 tumor xenografts. Importantly, AMG 900 was broadly active in multiple xenograft models, including 3 multidrug-resistant xenograft models, representing 5 tumor types. AMG 900 has entered clinical evaluation in adult patients with advanced cancers and has the potential to treat tumors refractory to anticancer drugs such as the taxanes.
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Preclinical Evaluation of AMG 900, a Novel Potent and Highly Selective Pan-Aurora Kinase Inhibitor with Activity in Taxane-Resistant Tumor Cell Lines
Cancer research, 2010Co-Authors: Marc Payton, Tammy L. Bush, Grace Tin-yun Chung, Beth Ziegler, Patrick Eden, Patricia Mcelroy, Sandra Ross, Victor J. Cee, Holly L. Deak, Brian L. HodousAbstract:Findings illustrate the nature of an Aurora Kinase Inhibitor that is distinct from others being studied in this class, in its being active in tumor cells that are resistant to traditional antimitotic drugs such as taxanes.
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Discovery of a potent, selective, and orally bioavailable pyridinyl-pyrimidine phthalazine Aurora Kinase Inhibitor.
Journal of medicinal chemistry, 2010Co-Authors: Victor J. Cee, Holly L. Deak, Brian L. Hodous, Laurie B. Schenkel, Hanh Nho Nguyen, Philip R. Olivieri, Karina Romero, Annette Bak, Steve BellonAbstract:The discovery of Aurora Kinases as essential regulators of cell division has led to intense interest in identifying small molecule Aurora Kinase Inhibitors for the potential treatment of cancer. A high-throughput screening effort identified pyridinyl-pyrimidine 6a as a moderately potent dual Inhibitor of Aurora Kinases -A and -B. Optimization of this hit resulted in an anthranilamide lead (6j) that possessed improved enzyme and cellular activity and exhibited a high level of Kinase selectivity. However, this anthranilamide and subsequent analogues suffered from a lack of oral bioavailability. Converting the internally hydrogen-bonded six-membered pseudo-ring of the anthranilamide to a phthalazine (8a−b) led to a dramatic improvement in oral bioavailability (38−61%F) while maintaining the potency and selectivity characteristics of the anthranilamide series. In a COLO 205 tumor pharmacodynamic assay measuring phosphorylation of the Aurora-B substrate histone H3 at serine 10 (p-histone H3), oral administrati...
