Grincamycins (GCNs) are a class of angucycline glycosides isolated from actinomycete Streptomyces strains that have potent antitumor activities,but their antitumor mechanisms remain unknown.In this study,we tried to identify the cellular target of grincamycin B (GCN B),one of most dominant and active secondary metabolites,using a combined strategy.We showed that GCN B-selective-induced apoptosis of human acute promyelocytic leukemia (APL) cell line NB4 through increase of ER stress and intracellular reactive oxygen species (ROS) accumulation.Using a strategy of combining phenotype,transcriptomics and protein microarray approaches,we identified that isocitrate dehydrogenase 1(IDH1) was the putative target of GCN B,and confirmed that GCNs were a subset of selective inhibitors targeting both wild-type and mutant IDH1 in vitro.It is well-known that IDH1 converts isocitrate to 2-oxoglutarate (2-OG),maintaining intracellular 2-OG homeostasis.IDH1 and its mutant as the target ofGCN B were validated in NB4 cells and zebrafish model.Knockdown of IDH1 in NB4 cells caused the similar phenotype as GCN B treatment,and supplementation of N-acetylcysteine partially rescued the apoptosis caused by IDH1 interference in NB4 cells.In zebrafish model,GCN B effectively restored myeloid abnormality caused by overexpression of mutant IDH1 (R132C).Taken together,we demonstrate that IDH1 is one of the antitumor targets of GCNs,suggesting wild-type IDH1 may be a potential target for hematological malignancies intervention in the future.