Michael J Morrison

Publications (5)47.44 Total impact

• Article: Discovery of 2,4-bis-arylamino-1,3-pyrimidines as insulin-like growth factor-1 receptor (IGF-1R) inhibitors.

  John L Buchanan, John R Newcomb, David P Carney, Stuart C Chaffee, Lilly Chai, Rod Cupples, Linda F Epstein, Paul Gallant, Yan Gu, Jean-Christophe Harmange, [......], Robert Radinsky, Paul E Rose, Satin Sawant, Ji-Rong Sun, Sekhar Surapaneni, Susan M Turci, Keyang Xu, Evelyn Yanez, Huilin Zhao, Xiaotian Zhu
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  ABSTRACT: The insulin-like growth factor-1 receptor (IGF-1R) plays an important role in the regulation of cell growth and differentiation, and in protection from apoptosis. IGF-1R has been shown to be an appealing target for the treatment of human cancer. Herein, we report the synthesis, structure-activity relationships (SAR), X-ray cocrystal structure and in vivo tumor study results for a series of 2,4-bis-arylamino-1,3-pyrimidines.
  Bioorganic & medicinal chemistry letters 02/2011; 21(8):2394-9. · 2.65 Impact Factor
• Article: Discovery of a potent, selective, and orally bioavailable pyridinyl-pyrimidine phthalazine aurora kinase inhibitor.

  Victor J Cee, Laurie B Schenkel, Brian L Hodous, Holly L Deak, Hanh N Nguyen, Philip R Olivieri, Karina Romero, Annette Bak, Xuhai Be, Steve Bellon, [......], Michael J Morrison, Vinod F Patel, Robert Radinsky, Paul E Rose, Sandra Ross, Ji-Rong Sun, Jin Tang, Huilin Zhao, Marc Payton, Stephanie D Geuns-Meyer
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  ABSTRACT: 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 administration of 8b at 50 mg/kg demonstrated significant reduction in tumor p-histone H3 for at least 6 h.
  Journal of Medicinal Chemistry 09/2010; 53(17):6368-77. · 4.80 Impact Factor
• Article: Novel 2,3-dihydro-1,4-benzoxazines as potent and orally bioavailable inhibitors of tumor-driven angiogenesis.

  Daniel S La, Julie Belzile, James V Bready, Angela Coxon, Thomas DeMelfi, Nicholas Doerr, Juan Estrada, Julie C Flynn, Shaun R Flynn, Russell F Graceffa, [......], Michael J Morrison, Vinod F Patel, Philip M Roveto, Ling Wang, Matthew M Weiss, Douglas A Whittington, Yohannes Teffera, Zhiyang Zhao, Anthony J Polverino, Jean-Christophe Harmange
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  ABSTRACT: Angiogenesis is vital for solid tumor growth, and its prevention is a proven strategy for the treatment of disease states such as cancer. The vascular endothelial growth factor (VEGF) pathway provides several opportunities by which small molecules can act as inhibitors of endothelial proliferation and migration. Critical to these processes is signaling through VEGFR-2 or the kinase insert domain receptor (KDR) upon stimulation by its ligand VEGF. Herein, we report the discovery of 2,3-dihydro-1,4-benzoxazines as inhibitors of intrinsic KDR activity (IC 50 < 0.1 microM) and human umbilical vein endothelial cell (HUVEC) proliferation with IC 50 < 0.1 microM. More specifically, compound 16 was identified as a potent (KDR: < 1 nM and HUVEC: 4 nM) and selective inhibitor that exhibited efficacy in angiogenic in vivo models. In addition, this series of molecules is typically well-absorbed orally, further demonstrating the 2,3-dihydro-1,4-benzoxazine moiety as a promising platform for generating kinase-based antiangiogenic therapeutic agents.
  Journal of Medicinal Chemistry 03/2008; 51(6):1695-705. · 5.25 Impact Factor
• Source

  Available from: Stephanie Pritchard

  Article: A quantitative analysis of kinase inhibitor selectivity.

  Mazen W Karaman, Sanna Herrgard, Daniel K Treiber, Paul Gallant, Corey E Atteridge, Brian T Campbell, Katrina W Chan, Pietro Ciceri, Mindy I Davis, Philip T Edeen, [......], Mark Floyd, Jeremy P Hunt, Daniel J Lockhart, Zdravko V Milanov, Michael J Morrison, Gabriel Pallares, Hitesh K Patel, Stephanie Pritchard, Lisa M Wodicka, Patrick P Zarrinkar
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  ABSTRACT: Kinase inhibitors are a new class of therapeutics with a propensity to inhibit multiple targets. The biological consequences of multi-kinase activity are poorly defined, and an important step toward understanding the relationship between selectivity, efficacy and safety is the exploration of how inhibitors interact with the human kinome. We present interaction maps for 38 kinase inhibitors across a panel of 317 kinases representing >50% of the predicted human protein kinome. The data constitute the most comprehensive study of kinase inhibitor selectivity to date and reveal a wide diversity of interaction patterns. To enable a global analysis of the results, we introduce the concept of a selectivity score as a general tool to quantify and differentiate the observed interaction patterns. We further investigate the impact of panel size and find that small assay panels do not provide a robust measure of selectivity.
  Nature Biotechnology 01/2008; 26(1):127-32. · 29.50 Impact Factor
• Article: Novel 2-aminopyrimidine carbamates as potent and orally active inhibitors of Lck: synthesis, SAR, and in vivo antiinflammatory activity.

  Matthew W Martin, John Newcomb, Joseph J Nunes, David C McGowan, David M Armistead, Christina Boucher, John L Buchanan, William Buckner, Lilly Chai, Daniel Elbaum, [......], Huilin Zhao, Li Zhu, Xiaotian Zhu, Chiara Ghiron, Patricia Amouzegh, Monika Ermann, James Jenkins, David Johnston, Spencer Napier, Eoin Power
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  ABSTRACT: The lymphocyte-specific kinase (Lck) is a cytoplasmic tyrosine kinase of the Src family expressed in T cells and NK cells. Genetic evidence in both mice and humans demonstrates that Lck kinase activity is critical for signaling mediated by the T cell receptor (TCR), which leads to normal T cell development and activation. A small molecule inhibitor of Lck is expected to be useful in the treatment of T cell-mediated autoimmune and inflammatory disorders and/or organ transplant rejection. In this paper, we describe the synthesis, structure-activity relationships, and pharmacological characterization of 2-aminopyrimidine carbamates, a new class of compounds with potent and selective inhibition of Lck. The most promising compound of this series, 2,6-dimethylphenyl 2-((3,5-bis(methyloxy)-4-((3-(4-methyl-1-piperazinyl)propyl)oxy)phenyl)amino)-4-pyrimidinyl(2,4-bis(methyloxy)phenyl)carbamate (43) exhibits good activity when evaluated in in vitro assays and in an in vivo model of T cell activation.
  Journal of Medicinal Chemistry 09/2006; 49(16):4981-91. · 5.25 Impact Factor