Veeraswamy Manne

Publications (8)30.51 Total impact

• Article: Design, synthesis and structure-activity relationships of novel biarylamine-based Met kinase inhibitors.

  David K Williams, Xiao-Tao Chen, Christine Tarby, Robert Kaltenbach, Zhen-Wei Cai, John S Tokarski, Yongmi An, John S Sack, Barri Wautlet, Johnni Gullo-Brown, Benjamin J Henley, Robert Jeyaseelan, Kristen Kellar, Veeraswamy Manne, George L Trainor, Louis J Lombardo, Joseph Fargnoli, Robert M Borzilleri
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  ABSTRACT: Biarylamine-based inhibitors of Met kinase have been identified. Lead compounds demonstrate nanomolar potency in Met kinase biochemical assays and significant activity in the Met-driven GTL-16 human gastric carcinoma cell line. X-ray crystallography revealed that these compounds adopt a bioactive conformation, in the kinase domain, consistent with that previously seen with 2-pyridone-based Met kinase inhibitors. Compound 9b demonstrated potent in vivo antitumor activity in the GTL-16 human tumor xenograft model.
  Bioorganic & medicinal chemistry letters 01/2010; 20(9):2998-3002. · 2.65 Impact Factor
• Article: Discovery of N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607), a selective and orally efficacious inhibitor of the Met kinase superfamily.

  Gretchen M Schroeder, Yongmi An, Zhen-Wei Cai, Xiao-Tao Chen, Cheryl Clark, Lyndon A M Cornelius, Jun Dai, Johnni Gullo-Brown, Ashok Gupta, Benjamin Henley, [......], Kevin Stefanski, John S Tokarski, George L Trainor, Barri S Wautlet, Donna Wei, David K Williams, Yingru Zhang, Yueping Zhang, Joseph Fargnoli, Robert M Borzilleri
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  ABSTRACT: Substituted N-(4-(2-aminopyridin-4-yloxy)-3-fluoro-phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamides were identified as potent and selective Met kinase inhibitors. Substitution of the pyridine 3-position gave improved enzyme potency, while substitution of the pyridone 4-position led to improved aqueous solubility and kinase selectivity. Analogue 10 demonstrated complete tumor stasis in a Met-dependent GTL-16 human gastric carcinoma xenograft model following oral administration. Because of its excellent in vivo efficacy and favorable pharmacokinetic and preclinical safety profiles, 10 has been advanced into phase I clinical trials.
  Journal of Medicinal Chemistry 04/2009; 52(5):1251-4. · 4.80 Impact Factor
• Article: Discovery of pyrrolopyridine-pyridone based inhibitors of Met kinase: synthesis, X-ray crystallographic analysis, and biological activities.

  Kyoung Soon Kim, Liping Zhang, Robert Schmidt, Zhen-Wei Cai, Donna Wei, David K Williams, Louis J Lombardo, George L Trainor, Dianlin Xie, Yaquan Zhang, [......], Yueping Zhang, Jonathan Lippy, Robert Jeyaseelan, Barri Wautlet, Benjamin Henley, Johnni Gullo-Brown, Veeraswamy Manne, John T Hunt, Joseph Fargnoli, Robert M Borzilleri
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  ABSTRACT: Conformationally constrained 2-pyridone analogue 2 is a potent Met kinase inhibitor with an IC50 value of 1.8 nM. Further SAR of the 2-pyridone based inhibitors of Met kinase led to potent 4-pyridone and pyridine N-oxide inhibitors such as 3 and 4. The X-ray crystallographic data of the inhibitor 2 bound to the ATP binding site of Met kinase protein provided insight into the binding modes of these inhibitors, and the SAR of this series of analogues was rationalized. Many of these analogues showed potent antiproliferative activities against the Met dependent GTL-16 gastric carcinoma cell line. Compound 2 also inhibited Flt-3 and VEGFR-2 kinases with IC50 values of 4 and 27 nM, respectively. It possesses a favorable pharmacokinetic profile in mice and demonstrates significant in vivo antitumor activity in the GTL-16 human gastric carcinoma xenograft model.
  Journal of Medicinal Chemistry 10/2008; 51(17):5330-41. · 4.80 Impact Factor
• Article: Discovery of orally active pyrrolopyridine- and aminopyridine-based Met kinase inhibitors.

  Zhen-Wei Cai, Donna Wei, Gretchen M Schroeder, Lyndon A M Cornelius, Kyoung Kim, Xiao-Tao Chen, Robert J Schmidt, David K Williams, John S Tokarski, Yongmi An, John S Sack, Veeraswamy Manne, Amrita Kamath, Yueping Zhang, Punit Marathe, John T Hunt, Louis J Lombardo, Joseph Fargnoli, Robert M Borzilleri
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  ABSTRACT: A series of acylurea analogs derived from pyrrolopyridine and aminopyridine scaffolds were identified as potent inhibitors of Met kinase activity. The SAR at various positions of the two kinase scaffolds was investigated. These studies led to the discovery of compounds 3b and 20b, which demonstrated favorable pharmacokinetic properties in mice and significant antitumor activity in a human gastric carcinoma xenograft model.
  Bioorganic & medicinal chemistry letters 07/2008; 18(11):3224-9. · 2.65 Impact Factor
• Article: Identification of pyrrolo[2,1-f][1,2,4]triazine-based inhibitors of Met kinase.

  Gretchen M Schroeder, Xiao-Tao Chen, David K Williams, David S Nirschl, Zhen-Wei Cai, Donna Wei, John S Tokarski, Yongmi An, John Sack, Zhong Chen, [......], Michael Poss, Barri Wautlet, Johnni Gullo-Brown, Kristen Kellar, Veeraswamy Manne, John T Hunt, Tai W Wong, Louis J Lombardo, Joseph Fargnoli, Robert M Borzilleri
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  ABSTRACT: An amide library derived from the pyrrolo[2,1-f][1,2,4]triazine scaffold led to the identification of modest inhibitors of Met kinase activity. Introduction of polar side chains at C-6 of the pyrrolotriazine core provided significant improvements in in vitro potency. The amide moiety could be replaced with acylurea and malonamide substituents to give compounds with improved potency in the Met-driven GTL-16 human gastric carcinoma cell line. Acylurea pyrrolotriazines with substitution at C-5 demonstrated single digit nanomolar kinase activity. X-ray crystallography revealed that the C-5 substituted pyrrolotriazines bind to the Met kinase domain in an ATP-competitive manner.
  Bioorganic & medicinal chemistry letters 04/2008; 18(6):1945-51. · 2.65 Impact Factor
• Article: Pyrrolopyridazine MEK inhibitors.

  Zhong Chen, Soong-Hoon Kim, Stephanie A Barbosa, Tram Huynh, David R Tortolani, Kenneth J Leavitt, Donna D Wei, Veeraswamy Manne, Carolyn S Ricca, Johnni Gullo-Brown, Michael A Poss, Wayne Vaccaro, Mark E Salvati
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  ABSTRACT: The synthesis and SAR of a series of pyrrolopyridazine MEK inhibitors are reported. Optimal activity was achieved by incorporation of a 4-phenoxyaniline substituent at C4 and an acylated amine at C6.
  Bioorganic & Medicinal Chemistry Letters 03/2006; 16(3):628-32. · 2.55 Impact Factor
• Article: Design, synthesis, and structure-activity relationships of tetrahydroquinoline-based farnesyltransferase inhibitors.

  Louis J Lombardo, Amy Camuso, John Clark, Krista Fager, Johnni Gullo-Brown, John T Hunt, Ivan Inigo, David Kan, Barry Koplowitz, Francis Lee, [......], Ligang Qian, Carolyn Ricca, George Rovnyak, Sarah Traeger, John Tokarski, David K Williams, Laurence I Wu, Yufen Zhao, Veeraswamy Manne, Rajeev S Bhide
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  ABSTRACT: Tetrahydroquinoline-based small molecule inhibitors of farnesyltransferase (FT) have been identified. Lead compounds were shown to have nanomolar to sub-nanomolar activity in biochemical assays with excellent potency in a Ras-mutated cellular reversion assay. BMS-316810 (9e), a 0.7 nM FT inhibitor, was orally-active in a nude mouse tumor allograft efficacy study.
  Bioorganic & Medicinal Chemistry Letters 05/2005; 15(7):1895-9. · 2.55 Impact Factor
• Article: Apoptotic and cytostatic farnesyltransferase inhibitors have distinct pharmacology and efficacy profiles in tumor models.

  Veeraswamy Manne, Francis Y F Lee, David K Bol, Johnni Gullo-Brown, Craig R Fairchild, Louis J Lombardo, Richard A Smykla, Gregory D Vite, Mei-Li D Wen, Chiang Yu, Tai Wai Wong, John T Hunt
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  ABSTRACT: BMS-214662 and BMS-225975 are tetrahydrobenzodiazepine-based farnesyltransferase inhibitors (FTIs) that have nearly identical structures and very similar pharmacological profiles associated with farnesyltransferase (FT) inhibition. Despite their similar activity against FT in vitro and in cells, these compounds differ dramatically in their apoptotic potency and tumor-regressing activity in vivo. BMS-214662 is the most potent apoptotic FTI known and exhibits curative responses in mice bearing a variety of staged human tumor xenografts such as HCT-116 human colon tumor. By contrast, BMS-225975 does not cause tumor regression and at best causes partial tumor growth inhibition in staged HCT-116 human colon tumor xenografts. Lack of tumor regression activity in BMS-225975 was attributable to its relatively weak apoptotic potency, not to poor cell permeability or pharmacokinetics. Both compounds were equally effective in inhibiting Ras processing and causing accumulation of a variety of nonfarnesylated substrates of FT in HCT-116 cells. Because BMS-225975 has poor apoptotic activity compared with BMS-214662 but inhibits FT to the same extent as BMS-214662, it is very unlikely that FT inhibition alone can account for the apoptotic potency of BMS-214662. Clearly distinct patterns of sensitivities in a cell line panel were obtained for the apoptotic FTI BMS-214662 and the cytostatic FTI BMS-225975. Activation of the c-Jun-NH(2)-terminal kinase pathway was readily observed with BMS-214662 but not with BMS-225975. We developed a highly sensitive San-1 murine xenograft tumor model that is particularly useful for evaluating the in vivo activity of cytostatic FTIs such as BMS-225975.
  Cancer Research 07/2004; 64(11):3974-80. · 7.86 Impact Factor