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International Journal of Hematology

, Volume 110, Issue 6, pp 699–708 | Cite as

Novel lysyl oxidase inhibitors attenuate hallmarks of primary myelofibrosis in mice

  • Orly Leiva
  • Seng Kah Ng
  • Shinobu Matsuura
  • Vipul Chitalia
  • Hector Lucero
  • Alison Findlay
  • Craig Turner
  • Wolfgang Jarolimek
  • Katya RavidEmail author
Original Article

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.

Keywords

Myelofibrosis Lysyl oxidase Myeloproliferative neoplasm 

Notes

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.

Compliance with ethical standards

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.

Supplementary material

12185_2019_2751_MOESM1_ESM.pdf (1.1 mb)
Supplementary material 1 (PDF 1108 kb)

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Copyright information

© Japanese Society of Hematology 2019

Authors and Affiliations

  1. 1.Department of Medicine and Whitaker Cardiovascular InstituteBoston University School of MedicineBostonUSA
  2. 2.Department of MedicineBrigham and Women’s HospitalBostonUSA
  3. 3.Renal Section, Department of MedicineBoston University School of MedicineBostonUSA
  4. 4.Pharmaxis Ltd.Frenchs ForestAustralia

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