Topical application of an irreversible small molecule inhibitor of lysyl oxidases ameliorates skin scarring and fibrosis

Nutan Chaudhari, Alison D. Findlay, Andrew W. Stevenson, Tristan D. Clemons, Yimin Yao, Amar Joshi, Sepidar Sayyar, Gordon Wallace, Suzanne Rea, Priyanka Toshniwal, Zhenjun Deng, Philip E. Melton, Nicole Hortin, K. Swaminathan Iyer, Wolfgang Jarolimek, Fiona M. Wood and Mark W. Fear ()
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Nutan Chaudhari: The University of Western Australia
Alison D. Findlay: Pharmaxis Ltd
Andrew W. Stevenson: The University of Western Australia
Tristan D. Clemons: The University of Western Australia
Yimin Yao: Pharmaxis Ltd
Amar Joshi: Pharmaxis Ltd
Sepidar Sayyar: University of Wollongong
Gordon Wallace: University of Wollongong
Suzanne Rea: Burns Service of Western Australia, WA, Department of Health
Priyanka Toshniwal: The University of Western Australia
Zhenjun Deng: The University of Western Australia
Philip E. Melton: University of Tasmania
Nicole Hortin: The University of Western Australia
K. Swaminathan Iyer: The University of Western Australia
Wolfgang Jarolimek: Pharmaxis Ltd
Fiona M. Wood: The University of Western Australia
Mark W. Fear: The University of Western Australia

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract Scarring is a lifelong consequence of skin injury, with scar stiffness and poor appearance presenting physical and psychological barriers to a return to normal life. Lysyl oxidases are a family of enzymes that play a critical role in scar formation and maintenance. Lysyl oxidases stabilize the main component of scar tissue, collagen, and drive scar stiffness and appearance. Here we describe the development and characterisation of an irreversible lysyl oxidase inhibitor, PXS-6302. PXS-6302 is ideally suited for skin treatment, readily penetrating the skin when applied as a cream and abolishing lysyl oxidase activity. In murine models of injury and fibrosis, topical application reduces collagen deposition and cross-linking. Topical application of PXS-6302 after injury also significantly improves scar appearance without reducing tissue strength in porcine injury models. PXS-6302 therefore represents a promising therapeutic to ameliorate scar formation, with potentially broader applications in other fibrotic diseases.

Date: 2022
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DOI: 10.1038/s41467-022-33148-5

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