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.

中文翻译：

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新型赖氨酰氧化酶抑制剂可减轻小鼠原发性骨髓纤维化的标志。

原发性骨髓纤维化（PMF）是一种慢性骨髓增生性肿瘤（MPN），通常预后较差，可用的治疗选择有限。目前，只有同种异体干细胞移植才能治愈，而施用JAK1 / 2抑制剂鲁索替尼有使血细胞减少症恶化的风险。可用的治疗选择有限，突出显示了开发针对PMF的新疗法的需求。赖氨酰氧化酶（LOX）是一种对胶原蛋白交联和细胞外基质硬化至关重要的酶，已发现在PMF中上调。在本文中，我们在两种PMF动物模型（GATA1low和JAK2V617F突变小鼠）中评估了两种新型LOX抑制剂PXS-LOX_1和PXS-LOX_2。特别，通过腹膜内注射以15 mg / kg的剂量将PXS-LOX_1或赋形剂给予15至16周龄的GATA1low小鼠，每周一次，四次，共9周。在雄性和雌性GATA1low小鼠中，与媒介物相比，发现PXS-LOX_1显着降低了骨髓纤维化负担和巨核细胞数量。根据这些结果，然后在15至17周大的JAK2V617F突变小鼠中以30 mg / kg的剂量每周四次检测PXS-LOX_1，共8周。同样，我们观察到了骨髓纤维化负担的显着降低。接下来，在15至17周龄的JAK2V617F突变小鼠中，以5 mg / kg的剂量每周口服4次，共8周，评估其口服生物利用度得到改善的LOX抑制剂PXS-LOX_2。该抑制剂还导致骨髓纤维化的显着减少，尽管雌性小鼠的改善更为明显。