Flonoltinib Maleate: A Comprehensive Profile of a Novel, Highly Selective JAK2/FLT3 Inhibitor for Myeloproliferative Neoplasms

Executive Summary

Flonoltinib maleate is an orally administered, investigational small molecule inhibitor representing a new generation of targeted therapy for myeloproliferative neoplasms (MPNs). Developed by Chengdu Zenitar Biomedical Technology Co., Ltd., Flonoltinib is engineered to overcome the limitations of existing Janus kinase (JAK) inhibitors through a novel and highly selective mechanism of action. It functions as a potent dual inhibitor of JAK2 and FMS-like tyrosine kinase 3 (FLT3), with a unique molecular interaction that involves simultaneous binding to both the active kinase domain (JH1) and the regulatory pseudokinase domain (JH2) of JAK2. This dual-domain engagement is the structural basis for its exceptional selectivity for JAK2 over other JAK family members, a feature designed to minimize off-target toxicities.

Preclinical studies have validated this mechanism, demonstrating potent anti-neoplastic activity in MPN cell lines and patient-derived cells, as well as superior efficacy in murine models of myelofibrosis, where it significantly reduced splenomegaly, suppressed bone marrow fibrosis, and prolonged survival. The drug exhibits a favorable preclinical pharmacokinetic profile characterized by good oral bioavailability and a primary hepato-biliary excretion pathway.