2. Academic Validation
  3. Identification and characterization of a potent and biologically-active PDE4/7 inhibitor via fission yeast-based assays

Identification and characterization of a potent and biologically-active PDE4/7 inhibitor via fission yeast-based assays

  • Cell Signal. 2017 Dec:40:73-80. doi: 10.1016/j.cellsig.2017.08.011.
Ana Santos de Medeiros 1,  Arlene R Wyman 2,  Manal A Alaamery 1,  Christina Allain 1,  F Douglas Ivey 1,  Lili Wang 1,  Hai Le 3,  James P Morken 4,  Alawi Habara 5,  Cuong Le 6,  Shuaiying Cui 7,  Adam Lerner 8,  Charles S Hoffman 9
Affiliations

Affiliations

  • 1 Biology Department, Boston College, 140 Commonwealth Ave., Chestnut Hill, MA 02467, USA.
  • 2 Biology Department, Boston College, 140 Commonwealth Ave., Chestnut Hill, MA 02467, USA. Electronic address: awpetri@mac.com.
  • 3 Chemistry Department, Boston College, 140 Commonwealth Ave., Chestnut Hill, MA 02467, USA.
  • 4 Chemistry Department, Boston College, 140 Commonwealth Ave., Chestnut Hill, MA 02467, USA. Electronic address: james.morken@bc.edu.
  • 5 Section of Hematology/Oncology, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA. Electronic address: habara@bu.edu.
  • 6 Section of Hematology/Oncology, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA. Electronic address: cuong@bu.edu.
  • 7 Section of Hematology/Oncology, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA. Electronic address: shuaiyin@bu.edu.
  • 8 Section of Hematology/Oncology, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA. Electronic address: lernwara@bu.edu.
  • 9 Biology Department, Boston College, 140 Commonwealth Ave., Chestnut Hill, MA 02467, USA. Electronic address: hoffmacs@bc.edu.
PMID: 28867658 DOI: 10.1016/j.cellsig.2017.08.011
Abstract

We previously constructed a collection of fission yeast strains that express various mammalian cyclic nucleotide phosphodiesterases (PDEs) and developed a cell-based high throughput screen (HTS) for small molecule PDE inhibitors. Here we describe a compound, BC54, that is a selective inhibitor of Enzymes from the cAMP-specific PDE4 and PDE7 families. Consistent with the biological effect of Other PDE4 and PDE7 inhibitors, BC54 displays potent anti-inflammatory properties and is superior to a combination of rolipram (a PDE4 Inhibitor) and BRL50481 (a PDE7A inhibitor) for inducing Apoptosis in chronic lymphocytic leukemia (CLL) cells. We further exploited PKA-regulated growth phenotypes in fission yeast to isolate two mutant alleles of the human PDE4B2 gene that encode Enzymes possessing single amino acid changes that confer partial resistance to BC54. We confirm this resistance to both BC54 and rolipram via yeast-based assays and, for PDE4B2T407A, in vitro enzyme assays. Thus, we are able to use this system for both chemical screens to identify biologically-active PDE inhibitors and molecular genetic studies to characterize the interaction of these molecules with their target Enzymes. Based on its potency, selectivity, and effectiveness in Cell Culture, BC54 should be a useful tool to study biological processes regulated by PDE4 and PDE7 Enzymes.

Keywords

High-throughput; Inflammation; PDE4; PDE7; Phosphodiesterase; Schizosaccharomyces pombe.

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