Eileen L Considine

Publications (8)29.92 Total impact

• Article: Erratum to: Discovery of LY2457546: a multi-targeted anti-angiogenic kinase inhibitor with a novel spectrum of activity and exquisite potency in the acute myelogenous leukemia-Flt-3-internal tandem duplication mutant human tumor xenograft model.

  Timothy P Burkholder, Joshua R Clayton, Mark E Rempala, James R Henry, John M Knobeloch, David Mendel, Johnathan A McLean, Yan Hao, David A Barda, Eileen L Considine, Mark T Uhlik, Yuefeng Chen, Liandong Ma, Laura J Bloem, Jacqueline K Akunda, Denis J McCann, Manuel Sanchez-Felix, David K Clawson, Michael M Lahn, James J Starling
  Investigational New Drugs 05/2011; · 3.36 Impact Factor
• Article: Discovery of LY2457546: a multi-targeted anti-angiogenic kinase inhibitor with a novel spectrum of activity and exquisite potency in the acute myelogenous leukemia-Flt-3-internal tandem duplication mutant human tumor xenograft model.

  Timothy P Burkholder, Joshua R Clayton, Mark E Rempala, James R Henry, John M Knobeloch, David Mendel, Johnathan A McLean, Yan Hao, David A Barda, Eileen L Considine, Mark T Uhlik, Yuefeng Chen, Liandong Ma, Laura J Bloem, Jacqueline K Akunda, Denis J McCann, Manuel Sanchez-Felix, David K Clawson, Michael M Lahn, James J Starling
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  ABSTRACT: LY2457546 is a potent and orally bioavailable inhibitor of multiple receptor tyrosine kinases involved in angiogenic and tumorigenic signalling. In biochemical and cellular assays, LY2457546 demonstrates potent activity against targets that include VEGFR2 (KDR), PDGFRβ, FLT-3, Tie-2 and members of the Eph family of receptors. With activities against both Tie2 and Eph receptors, LY2457546 possesses an activity profile that distinguishes it from multikinase inhibitors. When compared head to head with sunitinib, LY2457546 was more potent for inhibition of endothelial tube formation in an in vitro angiogenesis co-culture model with an intermittent treatment design. In vivo, LY2457546 inhibited VEGF-driven autophosphorylation of lung KDR in the mouse and rat in a dose and concentration dependent manner. LY2457546 was well tolerated and exhibited efficacy in a 13762 syngeneic rat mammary tumor model in both once and twice daily continuous dosing schedules and in mouse human tumor xenograft models of lung, colon, and prostate origin. Additionally, LY2457546 caused complete regression of well-established tumors in an acute myelogenous leukemia (AML) FLT3-ITD mutant xenograft tumor model. The observed efficacy that was displayed by LY2457546 in the AML FLT3-ITD mutant tumor model was superior to sunitinib when both were evaluated using equivalent doses normalized to in vivo inhibition of pKDR in mouse lung. LY2457546 was well tolerated in non-clinical toxicology studies conducted in rats and dogs. The majority of the toxicities observed were similar to those observed with other multi-targeted anti-angiogenic kinase inhibitors (MAKs) and included bone marrow hypocellularity, hair and skin depigmentation, cartilage dysplasia and lymphoid organ degeneration and necrosis. Thus, the unique spectrum of target activity, potent in vivo anti-tumor efficacy in a variety of rodent and human solid tumor models, exquisite potency against a clinically relevant model of AML, and non-clinical safety profile justify the advancement of LY2457546 into clinical testing.
  Investigational New Drugs 03/2011; 30(3):936-49. · 3.36 Impact Factor
• Article: Acyl sulfonamide anti-proliferatives: benzene substituent structure-activity relationships for a novel class of antitumor agents.

  Karen L Lobb, Philip A Hipskind, James A Aikins, Enrique Alvarez, Yiu-Yin Cheung, Eileen L Considine, Alfonso De Dios, Gregory L Durst, Rafael Ferritto, Cora Sue Grossman, [......], Luisa M Martin Cabrejas, Denis J McCann, Victoriano Molero, John E Reilly, Michael E Richett, Chuan Shih, Beverly Teicher, James H Wikel, Wesley T White, Mary M Mader
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  ABSTRACT: Two closely related diaryl acylsulfonamides were recently reported as potent antitumor agents against a broad spectrum of human tumor xenografts (colon, lung, breast, ovary, and prostate) in nude mice. Especially intriguing was their activity against colorectal cancer xenografts. In this paper, rapid parallel synthesis along with traditional medicinal chemistry techniques were used to quickly delineate the structure-activity relationships of the substitution patterns in both phenyl rings of the acylsufonamide anti-proliferative scaffold. Although the molecular target of the compounds remains unclear, we determined that the vascular endothelial growth factor-dependent human umbilical vein endothelial cells assay in combination with a soft agar disk diffusion assay allowed for optimization of potency in the series. The pharmacokinetic properties and in vivo activity in an HCT116 xenograft model are reported for representative compounds.
  Journal of Medicinal Chemistry 11/2004; 47(22):5367-80. · 5.25 Impact Factor
• Article: Preparation of novel aza-1,7-annulated indoles and their conversion to potent indolocarbazole kinase inhibitors.

  Rima S Al-awar, James E Ray, Kyle A Hecker, Sajan Joseph, Jianping Huang, Chuan Shih, Harold B Brooks, Charles D Spencer, Scott A Watkins, Richard M Schultz, Eileen L Considine, Margaret M Faul, Kevin A Sullivan, Stanley P Kolis, Michael A Carr, Faming Zhang
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  ABSTRACT: The synthesis of novel aza-1,7-annulated indoles was achieved and these were converted to indolocarbazoles that proved to be potent kinase inhibitors. These compounds were also evaluated in a human colon carcinoma cell line and proved to be good antiproliferative agents.
  Bioorganic & Medicinal Chemistry Letters 09/2004; 14(15):3925-8. · 2.55 Impact Factor
• Article: Synthesis of 1,7-annulated indoles and their applications in the studies of cyclin dependent kinase inhibitors.

  Guoxin Zhu, Scott E Conner, Xun Zhou, Ho-Kit Chan, Chuan Shih, Thomas A Engler, Rima S Al-Awar, Harold B Brooks, Scott A Watkins, Charles D Spencer, Richard M Schultz, Jack A Dempsey, Eileen L Considine, Bharvin R Patel, Catherine A Ogg, Vasu Vasudevan, Michelle L Lytle
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  ABSTRACT: The synthesis of a novel series of 1,7-annulated indolocarbazoles 2 and 16 is described. These compounds were found to be potent cyclin dependent kinase inhibitors with good antiproliferative activity against two human carcinoma cell lines. These inhibitors also arrested tumor cells at the G1 phase and inhibited pRb phosphorylation.
  Bioorganic & Medicinal Chemistry Letters 07/2004; 14(12):3057-61. · 2.55 Impact Factor
• Article: 1,7-annulated indolocarbazoles as cyclin-dependent kinase inhibitors.

  Rima S Al-awar, James E Ray, Kyle A Hecker, Jianping Huang, Philip P Waid, Chuan Shih, Harold B Brooks, Charles D Spencer, Scott A Watkins, Bharvin R Patel, Nancy B Stamm, Catherine A Ogg, Richard M Schultz, Eileen L Considine, Margaret M Faul, Kevin A Sullivan, Stanley P Kolis, John L Grutsch, Sajan Joseph
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  ABSTRACT: The synthesis and kinase inhibitory activity of a series of novel 1,7-annulated indolocarbazoles 6 and 16 is described. These compounds exhibited potent inhibitory activity against cyclin-dependent kinase 4 and good antiproliferative activity in a human colon carcinoma cell line.
  Bioorganic & Medicinal Chemistry Letters 07/2004; 14(12):3217-20. · 2.55 Impact Factor
• Article: Properties of bisphosphonates in the 13762 rat mammary carcinoma model of tumor-induced bone resorption.

  Enrique Alvarez, Michael Westmore, Rachelle J Sells Galvin, Crystal L Clapp, Eileen L Considine, Shawn J Smith, Kristan Keyes, Philip W Iversen, Dawn M Delafuente, Shola Sulaimon, Carmen Zambrano, Linda Ma, Masahiko Sato, T John Martin, Beverly A Teicher, Elizabeth J Galbreath
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  ABSTRACT: Bone metastasis from primary tumors is a clinically important complication of neoplastic progression. The role of parathyroid hormone-related protein (PTHrP) and transforming growth factor (TGF)-beta1 in this process has been clearly established. The current study describes an in vivo model of 13762 rat mammary carcinoma tumor cell-induced osteolysis in which PTHrP and TGF-beta1 expression is observed. Exposure of in vitro-cultured 13762 cells to doxorubicin, cis-platinum, carboplatin, methotrexate, 5-fluorouracil, paclitaxel, alendronate, risedronate, or pamidronate for 72 h resulted in varying effects on cell proliferation (IC(50) values of 0.005, 0.4, 1.9, >40, 17.9, 0.003, >40, >40, and 33.6 micro M, respectively). Tumor cells were implanted into the intramedullary space of the proximal tibia of rats, and the time course of tumor progression was evaluated using radiographic and microcomputed tomography scanning techniques. Trabecular bone mineral density, cortical bone mineral density, and whole bone mineral density were measured (in mg/cm(3)). In untreated animals, radiographic evidence of osteolysis was evident 7 days after implantation. Trabecular bone mineral density and whole bone mineral density were significantly decreased by 21 days after implantation (48% and 26%, respectively). Bisphosphonates showed broad protective activity against tumor-driven osteolysis, Immunohistochemical evaluation of s.c. and intratibially implanted cells demonstrated the expression of PTHrP and TGF-beta1. The results of this study demonstrate the ability of 13762 rat mammary carcinoma cells to elicit a measurable osteolysis and that bisphosphonates inhibit the tumor-induced bone resorption in this model.
  Clinical Cancer Research 11/2003; 9(15):5705-13. · 7.74 Impact Factor
• Article: Novel, potent and selective cyclin D1/CDK4 inhibitors: indolo[6,7-a]pyrrolo[3,4-c]carbazoles.

  Thomas A Engler, Kelly Furness, Sushant Malhotra, Concha Sanchez-Martinez, Chuan Shih, Walter Xie, Guoxin Zhu, Xun Zhou, Scott Conner, Margaret M Faul, [......], Charles D Spencer, Scott A Watkins, Eileen L Considine, Jack A Dempsey, Catherine A Ogg, Nancy B Stamm, Bryan D Anderson, Robert M Campbell, Vasu Vasudevan, Michelle L Lytle
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  ABSTRACT: The synthesis and CDK inhibitory properties of a series of indolo[6,7-a]pyrrolo[3,4-c]carbazoles is reported. In addition to their potent CDK activity, the compounds display antiproliferative activity against two human cancer cell lines. These inhibitors also effect strong G1 arrest in these cell lines and inhibit Rb phosphorylation at Ser780 consistent with inhibition of cyclin D1/CDK4.
  Bioorganic & Medicinal Chemistry Letters 08/2003; 13(14):2261-7. · 2.55 Impact Factor