Preclinical studies of Flonoltinib Maleate, a novel JAK2/FLT3 inhibitor, in treatment of JAK2V617F-induced myeloproliferative neoplasms

Mengshi Hu,Mingsong Shi,Zhuang Yang,Heying Pei,Ailin Zhao,Jinbing Zhu,Linyu Yang,Xue Yuan,Haoyu Ye,Minghai Tang,Qiang Chen,Jianhong Yang,Lu Niu,Ting Niu,Lijuan Chen,Tao Yang

doi:10.1038/s41408-022-00628-2

Mengshi Hu, Mingsong Shi + Show 14 more

Open Access

https://doi.org/10.1038/s41408-022-00628-2

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Abstract

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.

Highlights

Myeloproliferative neoplasms (MPNs) are a family of clonal disorders of hematopoietic stem cells featuring a continuous proliferation of one or more lineage cells in the bone marrow (BM) [1, 2]
We reported that a highly selective Janus kinase 2 (JAK2) inhibitor, named Flonoltinib Maleate (FM), had an inhibitory effect on JH1, JH2, and JH2V617F of JAK2, and its crystal structure confirmed that FM could stably bind to the JAK2 JH2 domain, which may contribute to the selectivity for the JAK family
FM exerting robust antitumor activity in Ba/F3-JAK2V617F disease model To further investigate the effect of FM, we evaluated the in vivo efficacy in an MPN-like Ba/F3-JAK2V617F mouse model, which was characterized by severe splenomegaly, extramedullary hematopoiesis, and reduced food intake

Summary

INTRODUCTION

Myeloproliferative neoplasms (MPNs) are a family of clonal disorders of hematopoietic stem cells featuring a continuous proliferation of one or more lineage cells in the bone marrow (BM) [1, 2]. Mutations of Janus kinase 2 (JAK2), predominantly JAK2V617F, are discovered in ~95% of patients with polycythemia vera and 50–60% of patients with essential thrombocythemia, as well as primary myelofibrosis (MF) [3–6] These previous results suggest that JAK2 is an important therapeutic target in the treatment of JAK2V617F-induced MPNs. Ruxolitinib, a JAK1/JAK2 inhibitor, is the first drug approved for the treatment of intermediate-2 and high-risk patients with MF and alleviates the splenomegaly and systemic symptoms in patients with MF [7–11]. We established a JAK2V617F bone marrow additional to primary cells acquired from patients with MPNs. In various MPN models, FM could significantly reduce tumor burden, suppress disease progression, and extend the survival of mice. FM has been approved by the National Medical Productions Administration of China (CXHL2000628), and this research will provide evidence for FM clinical trials in JAK2-driven MPN treatment

RESULTS

MATERIALS AND METHODS

Hu et al 3

DISCUSSION