Selective Inhibition of Collagen Prolyl 4-Hydroxylase in Human Cells
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- 作者：James D. Vasta ; Kristen A. Andersen ; Kathryn M. Deck ; Christopher P. Nizzi ; Richard S. Eisenstein ; Ronald T. Raines
- 刊名：ACS Chemical Biology
- 出版年：2016
- 出版时间：January 15, 2016
- 年：2016
- 卷：11
- 期：1
- 页码：193-199
- 全文大小：460K
- ISSN：1554-8937
文摘
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.