Selective Inhibition of Collagen Prolyl 4-Hydroxylase in Human Cells

ACS Chem Biol. 2016 Jan 15;11(1):193-9. doi: 10.1021/acschembio.5b00749. Epub 2015 Nov 19.


Collagen is the most abundant protein in animals. Its overproduction is associated with fibrosis and cancer metastasis. The stability of collagen relies on post-translational modifications, the most prevalent being the hydroxylation of collagen strands by collagen prolyl 4-hydroxylases (CP4Hs). Catalysis by CP4Hs enlists an iron cofactor to convert proline residues to 4-hydroxyproline residues, which are essential for the conformational stability of mature collagen. Ethyl 3,4-dihydroxybenzoate (EDHB) is commonly used as a "P4H" inhibitor in cells, but suffers from low potency, poor selectivity, and off-target effects that cause iron deficiency. Dicarboxylates of 2,2'-bipyridine are among the most potent known CP4H inhibitors but suffer from a high affinity for free iron. A screen of biheteroaryl compounds revealed that replacing one pyridyl group with a thiazole moiety retains potency and enhances selectivity. A diester of 2-(5-carboxythiazol-2-yl)pyridine-5-carboxylic acid is bioavailable to human cells and inhibits collagen biosynthesis at concentrations that neither cause general toxicity nor disrupt iron homeostasis. These data anoint a potent and selective probe for CP4H and a potential lead for the development of a new class of antifibrotic and antimetastatic agents.

Publication types

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

MeSH terms

  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / toxicity
  • Carboxylic Acids / chemistry
  • Carboxylic Acids / pharmacology*
  • Carboxylic Acids / toxicity
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Procollagen-Proline Dioxygenase / antagonists & inhibitors*
  • Procollagen-Proline Dioxygenase / chemistry
  • Thiazoles / chemistry
  • Thiazoles / pharmacology


  • Antineoplastic Agents
  • Carboxylic Acids
  • Enzyme Inhibitors
  • Thiazoles
  • Procollagen-Proline Dioxygenase