Pan-Lysyl Oxidase Inhibitor PXS-5505 Ameliorates Multiple-Organ Fibrosis by Inhibiting Collagen Crosslinks in Rodent Models of Systemic Sclerosis.

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  • Additional Information
    • Source:
      Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE
    • Publication Information:
      Original Publication: Basel, Switzerland : MDPI, [2000-
    • Subject Terms:
      Collagen*/antagonists & inhibitors ; Collagen*/metabolism ; Enzyme Inhibitors* ; Protein-Lysine 6-Oxidase*/antagonists & inhibitors ; Protein-Lysine 6-Oxidase*/metabolism ; Scleroderma, Systemic*/drug therapy ; Scleroderma, Systemic*/enzymology; Animals ; Disease Models, Animal ; Fibrosis ; Humans ; Mice ; Rodentia/metabolism
    • Abstract:
      Systemic sclerosis (SSc) is characterised by progressive multiple organ fibrosis leading to morbidity and mortality. Lysyl oxidases play a vital role in the cross-linking of collagens and subsequent build-up of fibrosis in the extracellular matrix. As such, their inhibition provides a novel treatment paradigm for SSc. A novel small molecule pan-lysyl oxidase inhibitor, PXS-5505, currently in clinical development for myelofibrosis treatment was evaluated using in vivo rodent models resembling the fibrotic conditions in SSc. Both lysyl oxidase and lysyl oxidase-like 2 (LOXL2) expression were elevated in the skin and lung of SSc patients. The oral application of PXS-5505 inhibited lysyl oxidase activity in the skin and LOXL2 activity in the lung. PXS-5505 exhibited anti-fibrotic effects in the SSc skin mouse model, reducing dermal thickness and α-smooth muscle actin. Similarly, in the bleomycin-induced mouse lung model, PXS-5505 reduced pulmonary fibrosis toward normal levels, mediated by its ability to normalise collagen/elastin crosslink formation. PXS-5505 also reduced fibrotic extent in models of the ischaemia-reperfusion heart, the unilateral ureteral obstruction kidney, and the CCl4-induced fibrotic liver. PXS-5505 consistently demonstrates potent anti-fibrotic efficacy in multiple models of organ fibrosis relevant to the pathogenesis of SSc, suggesting that it may be efficacious as a novel approach for treating SSc.
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    • Contributed Indexing:
      Keywords: fibrosis; lysyl oxidase; scleroderma; small molecule inhibitor
    • Accession Number:
      0 (Enzyme Inhibitors)
      9007-34-5 (Collagen)
      EC 1.4.3.13 (Protein-Lysine 6-Oxidase)
    • Publication Date:
      Date Created: 20220528 Date Completed: 20220531 Latest Revision: 20220716
    • Publication Date:
      20240829
    • Accession Number:
      PMC9146019
    • Accession Number:
      10.3390/ijms23105533
    • Accession Number:
      35628342