Study of Flonoltinib Maleate Tablets in the Treatment of Proliferative Bone Marrow Tumors

Flonoltinib Maleate (FM) targets Janus kinase 2 (JAK2) and FMS-like tyrosine kinase 3 (FLT3). FM is a dual target inhibitor of JAK2/FLT3.FM has the activity of inhibiting JAK2 signaling pathway, and pharmacodynamics evaluation also confirmed that FM has a good therapeutic effect on the primary splenomegaly model of mice induced by JAK2V617 mutation.Therefore, FM has the potential to treat bone marrow proliferative tumors.The drug is intended to be used in patients with MPN, mainly including medium-risk or high-risk myelofibrosis (FM) (including primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (PostPV-MF) and post-primary thrombocythemia myelofibrosis (postET-MF)), Polycythemia vera (PV) and essential thrombocythemia (ET) were the primary causes of thrombocythemia and thrombocythemia. FM has high inhibitory activity against JAK family and FLT3 kinase, suggesting that FM may have a certain therapeutic effect on AML disease.The IC50 of JAK2 kinase inhibition by FM was as low as 0.8 nM, while the IC50 of JAK1, JAK3 and Tyk2 kinase inhibition was 690 nM, 557 nM and 65nM, respectively. The selectivity of JAK2 kinase inhibition by FM was 862.5, 696.3 and 81.3 times, respectively. Therefore, FM showed highly selective inhibition of JAK2 kinase.The IC50 for FLT3 kinase was 15 nM. FM has better inhibitory activity against JAK2 kinase than the listed Ruxolitinib and Fedratinib, and has better selectivity against JAK family.In order to determine whether FM has targets other than JAK2 and Flt3 kinases, we tested FM's inhibitory activity against 100 human kinases that are highly associated with tumors, including some common drug-resistant mutant kinases.The results showed that, except for CDK4/6, LCK and LN, FM had no obvious inhibitory activity against the screened kinases at 0.1 μm, and no other targets were found. In vitro experiments on the proliferation of JAK2-dependent and Flt3-related tumor cell lines with FM showed that the tumor cell lines had a signi