Janus kinase 2 (JAK2) hyperactivation by JAK2V617F mutation leads to myeloproliferative neoplasms (MPNs) and targeting JAK2 could serve as a promising therapeutic strategy for MPNs. Here, we report that Flonoltinib Maleate (FM), a selective JAK2/FLT3 inhibitor, shows high selectivity for JAK2 over the JAK family. Surface plasmon resonance assays verified that FM had a stronger affinity for the pseudokinase domain JH2 than JH1 of JAK2 and had an inhibitory effect on JAK2 JH2V617F. The cocrystal structure confirmed that FM could stably bind to JAK2 JH2, and FM suppressed endogenous colony formation of primary erythroid progenitor cells from patients with MPNs. In several JAK2V617F-induced MPN murine models, FM could dose-dependently reduce hepatosplenomegaly and prolong survival. Similar results were observed in JAK2V617F bone marrow transplantation mice. FM exhibited strong inhibitory effects on fibrosis of the spleen and bone marrow. Long-term FM treatment showed good pharmacokinetic/pharmacodynamic characteristics with high drug exposure in tumor-bearing tissues and low toxicity. Currently, FM has been approved by the National Medical Products Administration of China (CXHL2000628), and this study will guide clinical trials for patients with MPNs.
Janus激酶2（JAK2）因JAK2V617F突变导致的过度活化会引发骨髓增殖性肿瘤（MPNs），靶向JAK2可作为MPNs的潜在治疗策略。本文报道了选择性JAK2/FLT3抑制剂马来酸氟诺替尼（FM）对JAK2具有高于JAK家族其他成员的选择性。表面等离子共振实验证实，FM与JAK2假激酶结构域JH2的亲和力强于激酶结构域JH1，并对JAK2 JH2V617F突变体具有抑制作用。共晶结构显示FM能稳定结合JAK2 JH2结构域，且在体外实验中能抑制MPNs患者原代红系祖细胞的内源性集落形成。在多种JAK2V617F诱导的MPN小鼠模型中，FM可剂量依赖性地减轻肝脾肿大并延长生存期。在JAK2V617F骨髓移植小鼠中也观察到类似效果。FM对脾脏和骨髓纤维化表现出显著抑制作用。长期给药显示FM具有良好的药代动力学/药效学特性，在荷瘤组织中药物暴露量高且毒性较低。目前该药物已获中国国家药品监督管理局批准（受理号CXHL2000628），本研究将为MPNs患者的临床试验提供指导。
肿瘤(癌症)患者之家