Rational Design of Inhibitors of Polyamine Synthesis

Summary

Principal Investigator: Steven Ealick
Abstract: The overall goal of this program project is to discover new cancer drugs that interfere with polyamine biosynthesis. Polyamines are ubiquitous cellular components and are necessary for normal cell growth. In humans, spermine and spermidine are the main polyamines. Previous studies, including numerous clinical trials, demonstrated that inhibition of polyamine biosynthesis is a valid target for cancer chemotherapy. In the proposed research, we will focus on S-adenosylmethionine decarboxylase (AdoMetDC), spermine/spermidine N1-acetyl transferase (SSAT) and the polyamine synthases, spermidine synthase and spermine synthase, as targets for structure-based drug design. AdoMetDC is a key regulatory enzyme in polyamine biosynthesis and levels of the enzyme vary rapidly in response to the cell cycle. The first AdoMetDC inhibitor to enter clinical trials, MGBG showed unexpected toxicity. More recently, clinical trials with SAM486A have been much more encouraging. We expect even further improvements with our structure-based approach. SSAT catalyzes the rate-limiting step in polyamine catabolism. It is highly inducible and has a very short half-life. Cellular levels of SSAT are increased by compounds that prevent its degradation. Some of these compounds have shown encouraging results in clinical trials. Spermidine synthase and permine synthase catalyze the final steps of polyamine biosynthesis. Inhibitors of the polyamine synthases have not yet entered clinical trials. In this program we will use the 3-D structures and iterative structure-based drug design to develop novel inhibitors of polyamine biosynthesis. The program consists of four projects, biochemistry (Dr. Pegg), crystallography (Dr. Ealick), modeling (Dr. Guida), and synthesis (Dr. Secrist), and two cores, administrative and animal testing. The administrative core will be responsible for program integration. Once we have identified potent in vitro inhibitors, further testing against standard tumor models will be carried out in the animal core. An external committee with expertise in clinical oncology will advise us on project priorities and potential clinical trials.
Funding Period: 2003-09-26 - 2009-08-31
more information: NIH RePORT

Top Publications

  1. pmc New insights into the design of inhibitors of human S-adenosylmethionine decarboxylase: studies of adenine C8 substitution in structural analogues of S-adenosylmethionine
    Diane E McCloskey
    Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA
    J Med Chem 52:1388-407. 2009
  2. pmc Binding and inhibition of human spermidine synthase by decarboxylated S-adenosylhomocysteine
    Jolita Seckute
    Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, USA
    Protein Sci 20:1836-44. 2011
  3. ncbi The crystal structure of 5'-deoxy-5'-methylthioadenosine phosphorylase II from Sulfolobus solfataricus, a thermophilic enzyme stabilized by intramolecular disulfide bonds
    Yan Zhang
    Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853 1301, USA
    J Mol Biol 357:252-62. 2006
  4. ncbi In silico chemical library screening and experimental validation of a novel 9-aminoacridine based lead-inhibitor of human S-adenosylmethionine decarboxylase
    Wesley H Brooks
    Drug Discovery Program, H Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA
    J Chem Inf Model 47:1897-905. 2007
  5. ncbi Computational validation of the importance of absolute stereochemistry in virtual screening
    Wesley H Brooks
    High Throughput Screening and Chemistry Core and Drug Discovery Program, H Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA
    J Chem Inf Model 48:639-45. 2008
  6. pmc Structural basis for putrescine activation of human S-adenosylmethionine decarboxylase
    Shridhar Bale
    Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, USA
    Biochemistry 47:13404-17. 2008
  7. pmc Role of the sulfonium center in determining the ligand specificity of human s-adenosylmethionine decarboxylase
    Shridhar Bale
    Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, USA
    Biochemistry 48:6423-30. 2009
  8. pmc Structural biology of S-adenosylmethionine decarboxylase
    Shridhar Bale
    Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY, 14853, USA
    Amino Acids 38:451-60. 2010
  9. pmc Complexes of Thermotoga maritimaS-adenosylmethionine decarboxylase provide insights into substrate specificity
    Shridhar Bale
    Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, USA
    Acta Crystallogr D Biol Crystallogr 66:181-9. 2010

Scientific Experts

  • Steven Ealick
  • Shridhar Bale
  • Diane E McCloskey
  • Anthony E Pegg
  • Wesley H Brooks
  • Wayne C Guida
  • John A Secrist
  • Jolita Seckute
  • Kenyon G Daniel
  • Yan Zhang
  • H Jeanette Thomas
  • Kavita Baba
  • Anita Tiwari
  • Jeremiah W Hanes
  • Arnold M Mahesan
  • Wesley Brooks
  • Thomas H Moss
  • Jacob Valiyaveettil
  • Qingming Fang
  • George I Makhatadze
  • Shen Shu Sung
  • Maria M Lopez
  • William R Waud
  • Giovanna Cacciapuoti
  • Marina Porcelli

Detail Information

Publications9

  1. pmc New insights into the design of inhibitors of human S-adenosylmethionine decarboxylase: studies of adenine C8 substitution in structural analogues of S-adenosylmethionine
    Diane E McCloskey
    Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA
    J Med Chem 52:1388-407. 2009
    ..To understand these results, we used computational modeling and X-ray crystallography to study C(8)-substituted adenine analogues bound in the active site...
  2. pmc Binding and inhibition of human spermidine synthase by decarboxylated S-adenosylhomocysteine
    Jolita Seckute
    Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, USA
    Protein Sci 20:1836-44. 2011
    ..1 ± 0.3 μM in the absence of putrescine and 3.2 ± 0.1 μM in the presence of putrescine. These results indicate a potential for further inhibitor development based on the dcSAH scaffold...
  3. ncbi The crystal structure of 5'-deoxy-5'-methylthioadenosine phosphorylase II from Sulfolobus solfataricus, a thermophilic enzyme stabilized by intramolecular disulfide bonds
    Yan Zhang
    Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853 1301, USA
    J Mol Biol 357:252-62. 2006
    ....
  4. ncbi In silico chemical library screening and experimental validation of a novel 9-aminoacridine based lead-inhibitor of human S-adenosylmethionine decarboxylase
    Wesley H Brooks
    Drug Discovery Program, H Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA
    J Chem Inf Model 47:1897-905. 2007
    ....
  5. ncbi Computational validation of the importance of absolute stereochemistry in virtual screening
    Wesley H Brooks
    High Throughput Screening and Chemistry Core and Drug Discovery Program, H Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA
    J Chem Inf Model 48:639-45. 2008
    ..Our results demonstrate that potential lead candidates may be overlooked when databases contain 3D structures representing only a single enantiomer of racemic chiral compounds...
  6. pmc Structural basis for putrescine activation of human S-adenosylmethionine decarboxylase
    Shridhar Bale
    Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, USA
    Biochemistry 47:13404-17. 2008
    ....
  7. pmc Role of the sulfonium center in determining the ligand specificity of human s-adenosylmethionine decarboxylase
    Shridhar Bale
    Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, USA
    Biochemistry 48:6423-30. 2009
    ..Stopped-flow kinetic experiments showed that the rate of the substrate binding to the enzyme greatly depends on Phe7 and Phe223, thus supporting the importance of the cation-pi interaction...
  8. pmc Structural biology of S-adenosylmethionine decarboxylase
    Shridhar Bale
    Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY, 14853, USA
    Amino Acids 38:451-60. 2010
    ..The residues implicated in processing and activity are structurally conserved in all forms of the enzyme, suggesting a divergent evolution of AdoMetDC...
  9. pmc Complexes of Thermotoga maritimaS-adenosylmethionine decarboxylase provide insights into substrate specificity
    Shridhar Bale
    Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, USA
    Acta Crystallogr D Biol Crystallogr 66:181-9. 2010
    ..The conservation of the ligand-binding mode and the active-site residues between human and T. maritima AdoMetDC provides insight into the evolution of AdoMetDC...