The DOI matches its Crossref record; 53 of the 53 references it cites were found in a registry or an index.
Selective Inhibition of Collagen Prolyl 4-Hydroxylase in Human Cells
Abstract
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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“Recently, we reported that certain dicarboxylate derivatives of 2,2′-bipyridine (bipy) and other biheteroaryl compounds are specific inhibitors of human CP4H.20,21”
From Human Collagen Prolyl 4-Hydroxylase Is Activated by Ligands for Its Iron Center (2016) · cites this paper as [21]
In the citing paper
“These biheteroaryl dicarboxylates compete with α-ketoglutarate for binding to the active-site iron.”
From Human Collagen Prolyl 4-Hydroxylase Is Activated by Ligands for Its Iron Center (2016) · cites this paper as [21]
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“For example, a thiazole analog (pythi) is a potent competitive inhibitor of CP4H1, whereas a pyrazole analog (pypyr) is not.”
From Human Collagen Prolyl 4-Hydroxylase Is Activated by Ligands for Its Iron Center (2016) · cites this paper as [21]
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“Moreover, the bipy core in these molecules can be replaced with chelating biheteroaryls.21”
From Human Collagen Prolyl 4-Hydroxylase Is Activated by Ligands for Its Iron Center (2016) · cites this paper as [21]
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Human Collagen Prolyl 4-Hydroxylase Is Activated by Ligands for Its Iron Center
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Self-citation
Metadata
- Authors
- Vasta, J. D., Andersen, K. A., Deck, K. M., Nizzi, C. P., Eisenstein, R. S., & Raines, R. T.
- Venue
- ACS Chemical Biology
- Publisher
- American Chemical Society (ACS)
- Published
- 2015-11-19
- Volume
- 11
- Issue
- 1
- Pages
- 193-199
- ISSN
- 1554-8929
- 1554-8937
- PMC
- PMC4798942
- Cited by
- 41
- References
- 53
- Language
- en
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK066600)
- Pharmaceutical Research and Manufacturers of America Foundation
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01 AR044276)
- National Institute of General Medical Sciences (P41 GM103399, T32 GM007215, T32 GM008688)
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