Discovery of FLT3-ITD Inhibitor Clifutinib: A Novel Biphenylacetylene Urea Derivative in Clinical Trials for the Treatment of Relapsed/Refractory FLT3-ITD+ Acute Myeloid Leukemia.

Internal tandem duplication (ITD) mutations of FLT3 (FLT3-ITD) are a promising target for patients with acute myeloid leukemia (AML), given that they have been identified in the majority of AML patients and are associated with poor prognosis. Here, a series of biphenylacetylene derivatives was developed as selective FLT3-ITD inhibitors. Representative compound 9e exhibited excellent potency against FLT3-ITD kinase, with an IC50 value of 15.1 nM, and potently suppressed the proliferation of MV-4-11 and MOLM-13 AML cells harboring FLT3-ITD, with IC50 values of 1.5 and 1.4 nM, respectively. Moreover, compound 9e displayed favorable drug-like properties and significantly suppressed tumor growth in MV-4-11 (1.5 mg/kg, qd, tumor growth inhibition (TGI) = 193.5%) and MOLM-13 (4.5 mg/kg, qd, TGI = 94%) xenograft tumor models in mice without significant weight loss. Compound 9e (named Clifutinib) is currently being evaluated in a phase III clinical trial (NCT05586074) for the treatment of relapsed/refractory FLT3-ITD-positive AML.