7F7W

JAK2-JH2

Summary for 7F7W

• Entry DOI: 10.2210/pdb7f7w/pdb
• Descriptor: Tyrosine-protein kinase JAK2, 2-((1-(2-fluoro-4-((4-(1-isopropyl-1H-pyrazol-4-yl)-5-methylpyrimidin-2-yl)amino)phenyl)piperidin-4-yl)(methyl)amino)ethan-1-ol (3 entities in total)
• Functional Keywords: jak2, jh2, inhibitor, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 64199.84

Authors

Niu, L. (deposition date: 2021-06-30, release date: 2022-03-30, Last modification date: 2024-10-09)

Primary citation

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.
Preclinical studies of Flonoltinib Maleate, a novel JAK2/FLT3 inhibitor, in treatment of JAK2 V617F -induced myeloproliferative neoplasms.
Blood Cancer J, 12:37-37, 2022

PubMed Abstract: Janus kinase 2 (JAK2) hyperactivation by JAK2 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 JAK2-induced MPN murine models, FM could dose-dependently reduce hepatosplenomegaly and prolong survival. Similar results were observed in JAK2 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.

PubMed: 35256594
DOI: 10.1038/s41408-022-00628-2

Experimental method

X-RAY DIFFRACTION (1.83 Å)