Collagen is the most abundant protein in animals and serves as the principle component of bone, connective tissues, and the extracellular matrix. A variety of diseases are associated with the overproduction of collagen including the fibrotic diseases and cancer metastasis. The stability of collagen relies heavily on post-translational modifications that occur throughout the secretory pathway. Arguably the most important of these modifications is the hydroxylation of collagen strands by collagen prolyl 4-hydroxylase (CP4H), an Fe(II)-a-ketoglutarate (AKG)-dependent dioxygenase (FAKGD) located in the lumen of the endoplasmic reticulum. Catalysis by CP4H converts (2S)-proline residues in protocollagen strands to (2S,4R)-4-hydroxyproline residues, which are essential for the conformational stability of mature collagen strands in vivo. Importantly, CP4H is a validated target for treatment of both the fibrotic diseases and metastatic breast cancer, which in aggregate represent a significant unmet clinical need. An effective therapy has yet to emerge from this strategy, due largely to the difficulty in designing selective inhibitors for enzymes of the FAKGD family. Herein, we report on the development of selective and bioavailable inhibitors of human CP4H. Using a chemical approach that takes advantage of newly developed methods in the palladium-catalyzed direct arylation of heterocycles, we redesign the classic 2,2'-bipyridine scaffold to generate potent biheteroaryl inhibitors of CP4H that are selective for enzymic iron. Further evaluation of these inhibitors in cell culture suggests that they are bioavailable and inhibit collagen synthesis at concentrations that do not disrupt iron homeostasis or cause general cytotoxicity. These results suggest the potential use of these inhibitors as leads for the development of antifibrotic and antimetastatic therapeutics.This work was supported by grant R01 AR044276 (NIH).

Selective and bioavailable inhibitors of collagen prolyl 4-hydroxylase

248th National Meeting (2014)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.