Discovery of a selective YTHDC1 inhibitor that targets acute myeloid leukemia

Abstract N6-methyladenosine (m 6 A) is the most prevalent modification of eukaryotic RNA, which is recognized by m 6 A-binding proteins (“readers”) and thereby mediates multiple biological processes. Dysregulation of the m 6 A readers has been linked to various pathologies, but the therapeutic potential of small molecule inhibitors targeting the m6A readers is unknown. Here we report the identification and characterization of a highly potent and selective first-in-class inhibitor (YL-5092) of YT521-B homology (YTH) domain-containing protein 1 (YTHDC1), which is a nuclear RNA m 6 A reader and plays essential roles in the pathological process of acute myeloid leukemia (AML). The crystal structure of YTHDC1 in complex with YL-5092 well explained its potency and selectivity. YL-5092 treatment substantially suppressed the proliferation and induced the differentiation and apoptosis of AML cells. It also efficiently inhibited the colony-forming ability of CD34 + AML stem cells, but had no effect on normal hematopoietic stem cells and early progenitors (Lin − Sca1 + Kit + ). Moreover, YL-5092 treatment impaired leukemogenesis and improved the animal survival rate in mouse AML xenograft models. Collectively, this research reveals a therapeutic potential of YTHDC1 inhibitors against AML, and provides proof of concept that targeting m 6 A readers represents a promising strategy for cancer treatment.