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Novel lysyl oxidase inhibitors attenuate hallmarks of primary myelofibrosis in mice

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Abstract

Primary myelofibrosis (PMF) is a chronic myeloproliferative neoplasm (MPN) that usually portends a poor prognosis with limited therapeutic options available. Currently, only allogeneic stem cell transplantation is curative in those who are candidates, while administration of the JAK1/2 inhibitor ruxolitinib carries a risk of worsening cytopenia. The limited therapeutic options available highlight the need for the development of novel treatments for PMF. Lysyl oxidase (LOX), an enzyme vital for collagen cross-linking and extracellular matrix stiffening, has been found to be upregulated in PMF. Herein, we evaluate two novel LOX inhibitors, PXS-LOX_1 and PXS-LOX_2, in two animal models of PMF (GATA1low and JAK2V617F-mutated mice). Specifically, PXS-LOX_1 or vehicle was given to 15- to 16-week-old GATA1low mice via intraperitoneal injection at a dose of 15 mg/kg four times a week for 9 weeks. PXS-LOX_1 was found to significantly decrease the bone marrow fibrotic burden and megakaryocyte number compared to vehicle in both male and female GATA1low mice. Given these results, PXS-LOX_1 was then tested in 15- to 17-week-old JAK2V617F-mutated mice at a dose of 30 mg/kg four times a week for 8 weeks. Again, we observed a significant decrease in bone marrow fibrotic burden. PXS-LOX_2, a LOX inhibitor with improved oral bioavailability, was next evaluated in 15- to 17-week-old JAK2V617F-mutated mice at a dose of 5 mg/kg p.o. four times a week for 8 weeks. This inhibitor also resulted in a significant decrease in bone marrow fibrosis, albeit with a more pronounced amelioration in female mice. Taking these results together, PXS-LOX_1 and PXS-LOX_2 appear to be promising new candidates for the treatment of fibrosis in PMF.

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Acknowledgements

This work was supported by a grant from Pharmaxis and by NIHLBI Grant R01HL136363 to KR. SKN was supported by a Cardiovascular Training grant T32 HL007224. OL was recipient of ASH Hematology Opportunities for the Next-Generation of Research Scientists (HONORS) Award from the American Society of Hematology.

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Author notes

  1. Orly Leiva, SengKah Ng and Shinobu Matsuura equally contributed to the study.

Authors and Affiliations

  1. Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, 700 Albany St., W-6, Boston, MA, 02118, USA

    Orly Leiva, Seng Kah Ng, Shinobu Matsuura, Hector Lucero & Katya Ravid

  2. Department of Medicine, Brigham and Women’s Hospital, Boston, MA, 02115, USA

    Orly Leiva

  3. Renal Section, Department of Medicine, Boston University School of Medicine, Boston, MA, 02118, USA

    Vipul Chitalia

  4. Pharmaxis Ltd., 20 Rodborough Road, Frenchs Forest, NSW, Australia

    Alison Findlay, Craig Turner & Wolfgang Jarolimek

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  1. Orly Leiva
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  2. Seng Kah Ng
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  3. Shinobu Matsuura
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  4. Vipul Chitalia
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  5. Hector Lucero
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  9. Katya Ravid
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Correspondence to Katya Ravid.

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Conflicts of interests

The authors declare that they have no conflict of interest. The authors affiliated with Pharmaxis synthesized and characterized the inhibitors and tested their efficacy in terms of inhibition of LOX in vivo, but were not involved in performing the experiments related to evaluation of fibrosis burden, and in interpretation of the results.

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Leiva, O., Ng, S.K., Matsuura, S. et al. Novel lysyl oxidase inhibitors attenuate hallmarks of primary myelofibrosis in mice. Int J Hematol 110, 699–708 (2019). https://doi.org/10.1007/s12185-019-02751-6

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  • DOI: https://doi.org/10.1007/s12185-019-02751-6

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