Paul Hughes

Publications (6)30.47 Total impact

• Article: Selective Class I Phosphoinositide 3-Kinase Inhibitors: Optimization of a Series of Pyridyltriazines Leading to the Identification of a Clinical Candidate, AMG 511.

  Mark H Norman, Kristin L Andrews, Yunxin Y Bo, Shon K Booker, Sean Caenepeel, Victor J Cee, Noel D D'Angelo, Daniel J Freeman, Bradley J Herberich, Fang-Tsao Hong, [......], Nuria A Tamayo, Ling Wang, Douglas A Whittington, Bin Wu, Tian Wu, Ryan P Wurz, Kevin Yang, Leeanne Zalameda, Nancy Zhang, Paul E Hughes
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  ABSTRACT: The phosphoinositide 3-kinase family catalyzes the phosphorylation of phosphatidylinositol-4,5-diphosphate to phosphatidylinositol-3,4,5-triphosphate, a secondary messenger which plays a critical role in important cellular functions such as metabolism, cell growth, and cell survival. Our efforts to identify potent, efficacious, and orally available phosphatidylinositol 3-kinase (PI3K) inhibitors as potential cancer therapeutics have resulted in the discovery of 4-(2-((6-methoxypyridin-3-yl)amino)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (1). In this paper, we describe the optimization of compound 1, which led to the design and synthesis of pyridyltriazine 31, a potent pan inhibitor of class I PI3Ks with a superior pharmacokinetic profile. Compound 31 was shown to potently block the targeted PI3K pathway in a mouse liver pharmacodynamic model and inhibit tumor growth in a U87 malignant glioma glioblastoma xenograft model. On the basis of its excellent in vivo efficacy and pharmacokinetic profile, compound 31 was selected for further evaluation as a clinical candidate and was designated AMG 511.
  Journal of Medicinal Chemistry 08/2012; 55(17):7796-816. · 4.80 Impact Factor
• Article: Discovery and optimization of a series of benzothiazole phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) dual inhibitors.

  Noel D D'Angelo, Tae-Seong Kim, Kristin Andrews, Shon K Booker, Sean Caenepeel, Kui Chen, Derin D'Amico, Dan Freeman, Jian Jiang, Longbin Liu, [......], Douglas A Whittington, Tian Wu, Ning Xi, Yang Xu, Peter Yakowec, Kevin Yang, Leeanne P Zalameda, Nancy Zhang, Paul Hughes, Mark H Norman
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  ABSTRACT: Phosphoinositide 3-kinase α (PI3Kα) is a lipid kinase that plays a key regulatory role in several cellular processes. The mutation or amplification of this kinase in humans has been implicated in the growth of multiple tumor types. Consequently, PI3Kα has become a target of intense research for drug discovery. Our studies began with the identification of benzothiazole compound 1 from a high throughput screen. Extensive SAR studies led to the discovery of sulfonamide 45 as an early lead, based on its in vitro cellular potency. Subsequent modifications of the central pyrimidine ring dramatically improved enzyme and cellular potency and led to the identification of chloropyridine 70. Further arylsulfonamide SAR studies optimized in vitro clearance and led to the identification of 82 as a potent dual inhibitor of PI3K and mTOR. This molecule exhibited potent enzyme and cell activity, low clearance, and high oral bioavailability. In addition, compound 82 demonstrated tumor growth inhibition in U-87 MG, A549, and HCT116 tumor xenograft models.
  Journal of Medicinal Chemistry 02/2011; 54(6):1789-811. · 4.80 Impact Factor
• Article: Context-dependent role of angiopoietin-1 inhibition in the suppression of angiogenesis and tumor growth: implications for AMG 386, an angiopoietin-1/2-neutralizing peptibody.

  Angela Coxon, James Bready, Hosung Min, Stephen Kaufman, Juan Leal, Dongyin Yu, Tani Ann Lee, Ji-Rong Sun, Juan Estrada, Brad Bolon, [......], Shao Xiong Wang, Anthony Ndifor, Isaac J Hayward, Beverly L Falcón, Donald M McDonald, Luke Li, Tom Boone, Richard Kendall, Robert Radinsky, Jonathan D Oliner
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  ABSTRACT: AMG 386 is an investigational first-in-class peptide-Fc fusion protein (peptibody) that inhibits angiogenesis by preventing the interaction of angiopoietin-1 (Ang1) and Ang2 with their receptor, Tie2. Although the therapeutic value of blocking Ang2 has been shown in several models of tumorigenesis and angiogenesis, the potential benefit of Ang1 antagonism is less clear. To investigate the consequences of Ang1 neutralization, we have developed potent and selective peptibodies that inhibit the interaction between Ang1 and its receptor, Tie2. Although selective Ang1 antagonism has no independent effect in models of angiogenesis-associated diseases (cancer and diabetic retinopathy), it induces ovarian atrophy in normal juvenile rats and inhibits ovarian follicular angiogenesis in a hormone-induced ovulation model. Surprisingly, the activity of Ang1 inhibitors seems to be unmasked in some disease models when combined with Ang2 inhibitors, even in the context of concurrent vascular endothelial growth factor inhibition. Dual inhibition of Ang1 and Ang2 using AMG 386 or a combination of Ang1- and Ang2-selective peptibodies cooperatively suppresses tumor xenograft growth and ovarian follicular angiogenesis; however, Ang1 inhibition fails to augment the suppressive effect of Ang2 inhibition on tumor endothelial cell proliferation, corneal angiogenesis, and oxygen-induced retinal angiogenesis. In no case was Ang1 inhibition shown to (a) confer superior activity to Ang2 inhibition or dual Ang1/2 inhibition or (b) antagonize the efficacy of Ang2 inhibition. These results imply that Ang1 plays a context-dependent role in promoting postnatal angiogenesis and that dual Ang1/2 inhibition is superior to selective Ang2 inhibition for suppression of angiogenesis in some postnatal settings.
  Molecular Cancer Therapeutics 10/2010; 9(10):2641-51. · 5.23 Impact Factor
• Article: Broad antitumor activity in breast cancer xenografts by motesanib, a highly selective, oral inhibitor of vascular endothelial growth factor, platelet-derived growth factor, and Kit receptors.

  Angela Coxon, Tammy Bush, Douglas Saffran, Stephen Kaufman, Brian Belmontes, Karen Rex, Paul Hughes, Sean Caenepeel, James B Rottman, Andrew Tasker, Vinod Patel, Richard Kendall, Robert Radinsky, Anthony Polverino
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  ABSTRACT: Angiogenesis plays a critical role in breast cancer development and progression. Vascular endothelial growth factor (VEGF) is a potent angiogenic factor that regulates endothelial cell proliferation and survival. We investigated the effects of motesanib, a novel, oral inhibitor of VEGF receptors 1, 2, and 3; platelet-derived growth factor receptor; and Kit receptor, on the growth of xenografts representing various human breast cancer subtypes. Athymic nude mice were implanted with MCF-7 (luminal) or MDA-MB-231 (mesenchymal) tumor fragments or Cal-51 (mixed/progenitor) tumor cells. Once tumors were established, animals were randomized to receive increasing doses of motesanib alone or motesanib plus cytotoxic chemotherapy (docetaxel, doxorubicin, or tamoxifen). Across all three xenograft models, motesanib treatment resulted in significant dose-dependent reductions in tumor growth, compared with vehicle-treated controls, and in marked reductions in viable tumor fraction and blood vessel density. No significant effect on body weight was observed with compound treatment compared with control-treated animals. Motesanib did not affect the proliferation of tumor cells in vitro. There was a significantly greater reduction in xenograft tumor growth when motesanib was combined with docetaxel (MDA-MB-231 tumors) or with the estrogen receptor modulator tamoxifen (MCF-7 tumors), compared with either treatment alone, but not when combined with doxorubicin (Cal-51 tumors). Treatment with motesanib alone or in combination with chemotherapy inhibits tumor growth in vivo in various models of human breast cancer. These data suggest that motesanib may have broad utility in the treatment of human breast cancer.
  Clinical Cancer Research 02/2009; 15(1):110-8. · 7.74 Impact Factor
• Article: Pyridyl-pyrimidine benzimidazole derivatives as potent, selective, and orally bioavailable inhibitors of Tie-2 kinase.

  Victor J Cee, Alan C Cheng, Karina Romero, Steve Bellon, Christopher Mohr, Douglas A Whittington, Annette Bak, James Bready, Sean Caenepeel, Angela Coxon, [......], Joseph L Kim, Jasmine Lin, Alexander M Long, Hanh Nguyen, Philip R Olivieri, Vinod F Patel, Ling Wang, Yihong Zhou, Paul Hughes, Stephanie Geuns-Meyer
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  ABSTRACT: Selective small molecule inhibitors of Tie-2 kinase are important tools for the validation of Tie-2 signaling in pathological angiogenesis. Reported herein is the optimization of a nonselective scaffold into a potent and highly selective inhibitor of Tie-2 kinase.
  Bioorganic & medicinal chemistry letters 12/2008; 19(2):424-7. · 2.65 Impact Factor
• Article: Alkynylpyrimidine amide derivatives as potent, selective, and orally active inhibitors of Tie-2 kinase.

  Victor J Cee, Brian K Albrecht, Stephanie Geuns-Meyer, Paul Hughes, Steve Bellon, James Bready, Sean Caenepeel, Stuart C Chaffee, Angela Coxon, Maurice Emery, [......], Alexander M Long, David McGowan, Michael Morrison, Philip R Olivieri, Vinod F Patel, Anthony Polverino, David Powers, Paul Rose, Ling Wang, Huilin Zhao
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  ABSTRACT: The recognition that aberrant angiogenesis contributes to the pathology of inflammatory diseases, cancer, and myocardial ischemia has generated considerable interest in the molecular mechanisms that regulate blood vessel growth. The receptor tyrosine kinase Tie-2 is expressed primarily by vascular endothelial cells and is critical for embryonic vasculogenesis. Interference with the Tie-2 pathway by diverse blocking agents such as soluble Tie-2 receptors, anti-Tie-2 intrabodies, anti-Ang-2 antibodies, and peptide-Fc conjugates has been shown to suppress tumor growth in xenograft studies. An alternative strategy for interfering with the Tie-2 signaling pathway involves direct inhibition of the kinase functions of the Tie-2 receptor. Herein we describe the development of alkynylpyrimidine amide derivatives as potent, selective, and orally available ATP-competitive inhibitors of Tie-2 autophosphorylation.
  Journal of Medicinal Chemistry 03/2007; 50(4):627-40. · 5.25 Impact Factor