Selective inhibition of prolyl 4-hydroxylases by bipyridinedicarboxylates

Bioorg Med Chem. 2015 Jul 1;23(13):3081-90. doi: 10.1016/j.bmc.2015.05.003. Epub 2015 May 11.


Collagen is the most abundant protein in animals. A variety of indications are associated with the overproduction of collagen, including fibrotic diseases and cancer metastasis. The stability of collagen relies on the posttranslational modification of proline residues to form (2S,4R)-4-hydroxyproline. This modification is catalyzed by collagen prolyl 4-hydroxylases (CP4Hs), which are Fe(II)- and α-ketoglutarate (AKG)-dependent dioxygenases located in the lumen of the endoplasmic reticulum. Human CP4Hs are validated targets for treatment of both fibrotic diseases and metastatic breast cancer. Herein, we report on 2,2'-bipyridinedicarboxylates as inhibitors of a human CP4H. Although most 2,2'-bipyridinedicarboxylates are capable of inhibition via iron sequestration, the 4,5'- and 5,5'-dicarboxylates were found to be potent competitive inhibitors of CP4H, and the 5,5'-dicarboxylate was selective in its inhibitory activity. Our findings clarify a strategy for developing CP4H inhibitors of clinical utility.

Keywords: Collagen; Hydroxyproline; Hypoxia-inducible factor; Iron; α-Ketoglutarate.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding, Competitive
  • Carboxylic Acids / chemical synthesis
  • Carboxylic Acids / chemistry*
  • Collagen / antagonists & inhibitors
  • Collagen / biosynthesis
  • Dose-Response Relationship, Drug
  • Enzyme Assays
  • Humans
  • Hypoxia-Inducible Factor-Proline Dioxygenases / antagonists & inhibitors*
  • Hypoxia-Inducible Factor-Proline Dioxygenases / chemistry
  • Iron / metabolism
  • Iron Chelating Agents / chemical synthesis
  • Iron Chelating Agents / chemistry*
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / chemistry
  • Kinetics
  • Procollagen-Proline Dioxygenase / antagonists & inhibitors*
  • Procollagen-Proline Dioxygenase / chemistry
  • Prolyl-Hydroxylase Inhibitors / chemical synthesis
  • Prolyl-Hydroxylase Inhibitors / chemistry*
  • Pyridines / chemical synthesis
  • Pyridines / chemistry*
  • Recombinant Proteins / chemistry


  • Carboxylic Acids
  • Iron Chelating Agents
  • Isoenzymes
  • Prolyl-Hydroxylase Inhibitors
  • Pyridines
  • Recombinant Proteins
  • Collagen
  • Iron
  • EGLN1 protein, human
  • Procollagen-Proline Dioxygenase
  • Hypoxia-Inducible Factor-Proline Dioxygenases