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Pan-Lysyl Oxidase Inhibitor PXS-5505 Ameliorates Multiple-Organ Fibrosis by Inhibiting Collagen Crosslinks in Rodent Models of Systemic Sclerosis.
Yao, Yimin; Findlay, Alison; Stolp, Jessica; Rayner, Benjamin; Ask, Kjetil; Jarolimek, Wolfgang.
Afiliação
  • Yao Y; Drug Discovery, Pharmaxis Ltd., Sydney, NSW 2086, Australia.
  • Findlay A; Drug Discovery, Pharmaxis Ltd., Sydney, NSW 2086, Australia.
  • Stolp J; Drug Discovery, Pharmaxis Ltd., Sydney, NSW 2086, Australia.
  • Rayner B; Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Kensington, Sydney, NSW 2031, Australia.
  • Ask K; Division of Respirology, Department of Medicine, McMaster University, Hamilton, ON L8N 3Z5, Canada.
  • Jarolimek W; Drug Discovery, Pharmaxis Ltd., Sydney, NSW 2086, Australia.
Int J Mol Sci ; 23(10)2022 May 16.
Article em En | MEDLINE | ID: mdl-35628342
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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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Escleroderma Sistêmico / Colágeno / Inibidores Enzimáticos / Proteína-Lisina 6-Oxidase Idioma: En Ano de publicação: 2022 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Escleroderma Sistêmico / Colágeno / Inibidores Enzimáticos / Proteína-Lisina 6-Oxidase Idioma: En Ano de publicação: 2022 Tipo de documento: Article