- Selective inhibition of prolyl 4-hydroxylases by bipyridinedicarboxylates
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Abstract Collagen is the most abundant protein in animals. A variety of indications are associated with the overproduction of collagen, including fibrotic diseases and cancer metastasis. The stability of collagen relies on the posttranslational modification of proline residues to form (2S,4R)-4-hydroxyproline. This modification is catalyzed by collagen prolyl 4-hydroxylases (CP4Hs), which are Fe(II)- and α-ketoglutarate (AKG)-dependent dioxygenases located in the lumen of the endoplasmic reticulum. Human CP4Hs are validated targets for treatment of both fibrotic diseases and metastatic breast cancer. Herein, we report on 2,2′-bipyridinedicarboxylates as inhibitors of a human CP4H. Although most 2,2′-bipyridinedicarboxylates are capable of inhibition via iron sequestration, the 4,5′- and 5,5′-dicarboxylates were found to be potent competitive inhibitors of CP4H, and the 5,5′-dicarboxylate was selective in its inhibitory activity. Our findings clarify a strategy for developing CP4H inhibitors of clinical utility.
- Vasta, James D.,Raines, Ronald T.
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- INHIBITORS OF COLLAGEN PROLYL 4-HYDROXYLASE
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Biheteroaryl dicarboxylates and esters, and salts thereof which are useful as modulators of CP4H activity and more particularly as inhibitors of CP4H. Compounds of formula: and salts thereof where: X is S, O, NH, or NR, where R is an alkyl group having 1-3 carbon atoms; R1 and R2 independently are —OR7, or —NHSO2R8, where R7 is selected from: hydrogen, alkyl, alkenyl, alkoxyalkyl, —R′—CO—R″, —R′—CO—O—R″, —CO—R″, —R′—O—CO—R″, —R′—CO—NR″, —CO—NR″, or —R′—O—CO—NR″, and R8 is selected from hydrogen, alkyl, aryl, arylalkyl; R3, R4 and R6 independently are hydrogen, alkyl, alkoxy, alkenyl, alkenoxy, halo alkyl, haloalkenyl, halogen, hydroxyl, hydroxyalkyl, hydroxyalkenyl, aryl, aryloxy, arylalkyl or arylalkyloxy; R5 is hydrogen, halogen, alkyl having 1-3 carbon atoms, or alkoxy having 1-3 carbon atoms; —R′— is a divalent straight chain or branched alkylene, and —R″ is an alkyl, alkenyl, arylalkyl, or aryl group. Methods for inhibition of CP4H in vivo and in vitro.
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Paragraph 0336; 0337; 0338
(2016/10/17)
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