Heterozygous mutations in genes encoding isocitrate dehydrogenase (IDH) 1 and 2 are frequently detected in acute myeloid leukemia (AML), angioimmunoblastic T-cell lymphoma, glioma, and cholangiocarcinoma. Mutant IDH catalyzes the formation of the oncometabolite D-2-hydroxyglutarate (D-2-HG). DS-1001b, a novel, orally bioavailable, selective mutant IDH1 inhibitor, impaired the proliferation of chondrosarcoma cells with IDH1 mutations in vitro and in vivo, and decreased 2-HG levels. Exposure to 1 μM DS-1001b for 72 h markedly decreased intracellular 2-HG levels in JJ012 and L835 cells. Intracellular D-2-HG levels were 100-fold higher than L-2-HG levels and completely blocked with 1 μM DS-1001b for 72 h in both IDH1-mutated cell lines. DS-1001b (0 - 10 μM) impaired proliferation in both cell lines in a dose-dependent manner. It decreased cell viability in a dose-dependent manner even under 3D and hypoxic conditions. Furthermore, treatment with different concentrations of DS-1001b for 72 h decreased intracellular 2-HG levels in a dose-dependent manner in JJ012 and L835 cells. In vivo, continuous administration of DS-1001b significantly impaired subcutaneous tumor growth in JJ012 xenograft mice. Moreover, 2-HG levels were markedly lower in DS-1001b-treated mice than in untreated mice (P < 0.001)[1].
搜索
