YL-5092 is a highly potent and selective, first-in-class inhibitor of RNA m6A reader YTHDC1 with IC50 of 7.4 nM and SPR Kd of 29.6 nM.
YL-5092 dose-dependently blocked the binding of substrate mimic, indicating a competitive inhibitor of substrate.
YL-5092 shows no activity against other RNA m6A readers, including YTHDC2, YTHDF1-3, IGF2BP1-3, and HNRNPA2B1.
YL-5092 treatment could dose-dependently stabilize YTHDC1 in MOLM-13 and U937 cells in cellular thermal shift assay (CETSA).
YL-5092 treatment substantially suppressed the proliferation and induced the differentiation and apoptosis of AML cells.
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+).
YL-5092 treatment impaired leukemogenesis and improved the animal survival rate in mouse AML xenograft models.
