Single Oral Administration of KRN383, a Novel Flt3 Inhibitor, Induces Eradication of the Xenograft Tumor Harboring Flt3 Mutation in Mice.

Constitutively activating mutations of the Flt3 receptor tyrosine kinase including internal tandem duplication (ITD) mutations are the most common genetic abnormality and are associated with a poor prognosis in acute myeloid leukemia (AML) patients. Therefore, Flt3 is a potential therapeutic target in AML. We show here the results of pre-clinical studies on KRN383, a novel orally active quinoline-urea derivative.

KRN383 inhibited autophosphorylation of ITD mutant (IC₅₀=1.3nM) and wild type (IC₅₀=0.4nM) Flt3 in the leukemia cell line MV4-11 and THP-1, respectively. KRN383 induced cell cycle arrest, apoptosis and suppression of proliferation (IC₅₀=0.8nM) of MV4-11 in vitro. Single (80mg/kg) or consecutive (20mg/kg/d X 28d) oral administration of KRN383 induced eradication (longer than 6mo) of tumor xenograft (MV4-11) subcutaneously implanted in all nude mice. All these effects were superior to those of SU11248, a precedent Flt3 inhibitor. In addition, single (80mg/kg) administration of KRN383 prolonged the survival of SCID mice to which MOLM-13 (ITD mutant positive leukemia cell line) was intravenously transplanted. The advantage of KRN383 over SU11248 was more obvious in in vitro studies in which the inhibition of Flt3 autophosphorylation and cellular proliferation induced by transient exposure with those drugs was determined. These results indicate that KRN383 has therapeutic potential in ITD mutant positive AML. Furthermore, eradication induced by single administration of KRN383 suggests that KRN383 provides feasibility to set wide variety of clinical regimens including multi-cycle and combination therapies. In vitro activity of Ki23819, hydrochloride salt of KRN383, is also to be reported in this ASH meeting (Komeno et al.).