生物活性

• 描述Acute myeloid leukemia (AML) is an aggressive hematologic disorder in which the hematopoietic progenitor cells lose their ability to differentiate normally and continue to proliferate. Fms-like tyrosine receptor kinase (FLT) 3 plays an important role in normal hematopoiesis and leukemogenesis and is expressed in most AML blasts. G-749 is a novel and effective FLT3 inhibitor with IC₅₀s of 0.4 nM, 0.6 nM and 1 nM for FLT3 (WT), FLT3 (D835Y) and Mer, respectively. G-749 inhibited autophosphorylation of FLT3 with an IC₅₀ value of ≤8 nM in FLT3-WT bearing RS4-11 and in FLT3-ITD harboring MV4-11 and Molm-14 cells. The antiproliferative activity of G-749 was assessed in several leukemia cell lines where it showed strong antiproliferation of leukemia cells addicted to FLT3-ITD (MV4-11 and Molm-14) in a dose-dependent manner. The BaF3 cells expressing the indicated FLT3 mutations were incubated for 2 h with G-749, and G-749 showed strong potency against autophosphorylation of all tested FLT3 mutants with IC₅₀ of <10 nM. A single dose of G-749 HCl salt (10 mg/kg) was administered orally to subcutaneous MV4-11 xenograft mice and showed sustained inhibition of p-FLT3, p-STAT5, and p-ERK1/2, which indicated that G-749 effectively inhibits the FLT3 pathway and that its inhibition lasts for 24 h. Antitumor efficacy was examined with the MV4-11 xenograft mice using G-749 HCl salt (administered orally every day for 28 days). Significant inhibition of tumor growth was observed in the 3 mg/kg per day dosing group from 4 days onward, and apparent tumor regression was seen in the 10 and 30 mg/kg per day dosing group.