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

Selective Inhibition of Collagen Prolyl 4-Hydroxylase in Human Cells.

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Department of Biochemistry, University of Wisconsin-Madison , 433 Babcock Drive, Madison, Wisconsin 53706, United States.
Graduate Program in Molecular and Cellular Pharmacology, University of Wisconsin-Madison , 1300 University Avenue, Madison, Wisconsin 53706, United States.
Department of Nutritional Sciences, University of Wisconsin-Madison , 1415 Linden Drive, Madison, Wisconsin 53706, United States.
Department of Chemistry, University of Wisconsin-Madison , 1101 University Avenue, Madison, Wisconsin 53706, United States.


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.

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