Open AccessNovel lysyl oxidase inhibitors attenuate hallmarks of primary myelofibrosis in mice
Author(s) -
Orly Leiva,
Seng Kah Ng,
Shinobu Matsuura,
Vipul C. Chitalia,
Héctor A. Lucero,
Alison D. Findlay,
Catherine Turner,
Wolfgang Jarolimek,
Katya Ravid
Publication year - 2019
Publication title -
international journal of hematology
Language(s) - English
Resource type - Journals
eISSN - 1865-3774
pISSN - 0925-5710
DOI - 10.1007/s12185-019-02751-6
Subject(s) - lysyl oxidase , myelofibrosis , medicine , bone marrow , myeloproliferative neoplasm , pharmacology , ruxolitinib , cancer research , extracellular matrix , chemistry , biochemistry
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.