Reference Detail

Ref Type

Journal Article

PMID

(35256594)

Authors

Hu M, Yang T, Yang L, Niu L, Zhu J, Zhao A, Shi M, Yuan X, Tang M, Yang J, Pei H, Yang Z, Chen Q, Ye H, Niu T, Chen L

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Blood cancer journal	12	3	2022 Mar 07	37	Blood Cancer J

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
Flonoltinib maleate	Flonoltinib maleate	7	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Flonoltinib maleate			FLT3 Inhibitor 69 JAK2 Inhibitor 19	Flonoltinib maleate inhibits JAK2 and FLT3, which potentially decreases downstream signaling and tumor growth (PMID: 35256594).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FLT3 exon 14 ins	acute myeloid leukemia	sensitive	Flonoltinib maleate	Preclinical - Cell culture	Actionable	In a preclinical study, Flonoltinib maleate inhibited Flt3 pathway signaling and cell cycle progression and induced apoptosis in acute myeloid leukemia cells harboring a FLT3-ITD in culture (PMID: 35256594).	35256594
JAK2 V617F	hematologic cancer	sensitive	Flonoltinib maleate	Preclinical	Actionable	In a preclinical study, Flonoltinib maleate inhibited Jak2 downstream signaling and proliferation and induced apoptosis in a cell line expressing JAK2 V617F in culture and increased survival in a mouse model (PMID: 35256594).	35256594
JAK2 V617F	myelofibrosis	sensitive	Flonoltinib maleate	Preclinical	Actionable	In a preclinical study, Flonoltinib maleate decreased splenomegaly and improved survival in a mouse model of myelofibrosis harboring JAK2 V617F (PMID: 35256594).	35256594
FLT3 exon 14 ins FLT3 D835V	hematologic cancer	sensitive	Flonoltinib maleate	Preclinical - Cell culture	Actionable	In a preclinical study, Flonoltinib maleate inhibited proliferation of a cell line expressing a FLT3-ITD and FLT3 D835V in culture (PMID: 35256594).	35256594
FLT3 exon 14 ins	hematologic cancer	sensitive	Flonoltinib maleate	Preclinical - Cell culture	Actionable	In a preclinical study, Flonoltinib maleate inhibited proliferation of a cell line expressing a FLT3-ITD in culture (PMID: 35256594).	35256594
JAK2 V617F	acute myeloid leukemia	sensitive	Flonoltinib maleate	Preclinical - Cell culture	Actionable	In a preclinical study, Flonoltinib maleate inhibited Jak/Stat signaling and cell cycle progression and induced apoptosis in an acute myeloid leukemia cell line harboring JAK2 V617F in culture (PMID: 35256594).	35256594
JAK2 V617F	myeloproliferative neoplasm	sensitive	Flonoltinib maleate	Preclinical - Cell culture	Actionable	In a preclinical study, Flonoltinib maleate inhibited Jak/Stat signaling and colony formation in myeloproliferative neoplasm patient-derived cells harboring JAK2 V617F in culture (PMID: 35256594).	35256594