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

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.

The Impact of JAK2 V617F, CALR, and MPL Mutations as Molecular Diagnostic Markers of Myeloproliferative Neoplasms in Kurdish Patients. A Single-center Experience

“…Based on studies, JAK2 V617F mutation was seen in 95% of PV patients and about 50-60% of ET and PMF patients (12,(17)(18)(19). In this study, it was shown that the frequency of JAK2 V617F mutation was 97.1% in PV patients, 50% in ET patients, and 60.25%in PMF patients.…”

The importance of protein domain mutations in cancer therapy

“…protein domains have been predicted as frequently mutated domains and reported in the DCMP database. Protein Domain Target Function Reference BCL-2* Anti-apoptotic protein Apoptosis [ 191 ] CDK4/6 Cyclin-dependent kinases Cell cycle regulation [ 192 ] EGFR Epidermal growth factor receptor Cell proliferation, angiogenesis [ 193 ] FLT3* FMS-like tyrosine kinase 3 Cell survival, proliferation [ 194 ] HER2 Human epidermal growth factor receptor 2 Cell proliferation, survival [ 195 ] IDH1 Isocitrate dehydrogenase 1 Metabolic reprogramming [ 196 ] JAK2 Janus kinase 2 Cell proliferation, differentiation [ 197 ] KRAS Kirsten rat sarcoma viral oncogene homolog Cell proliferation, survival [ 198 ] mTOR Mammalian target of rapamycin Cell growth, metabolism [ 199 ] NTRK Neurotrophic tyrosine receptor kinase Cell survival, differentiation [ 200 ] PD-L1 Programmed death-ligand 1 …”