inhibitors by incorporating the benzonitrile into the BI-9321 to replace the quinoline ring, which was thought that could achieve the binding selectivity of NSD2 over the NSD3 protein. Besides, we also noticed that the methyl group on the benzene ring of BI-9321 was at the similar position of the O atom of the amide group of MR837, and the distance between the methyl C atom on the benzene ring of BI-9321 and Tyr233 was 3.6 Å. We hypothesized that if the methyl on the benzene ring was replaced with methoxy group, the O atom of methoxyl group may be able to form a hydrogen bond with Tyr233. Taking together, we designed and synthesized compound 5 in Figure for the biological test to verify the design strategy.