In the NSD2-PWWP1 domain, there are Gly268, Asp269 and Ala270 residues forming hydrogen bonds with benzonitrile structure, while in NSD3-PWWP1 domain, at the same position, there are Ser314, Asn315 and Gln316 surrounding the quinolone ring of BI-9321. It should be noted that the side chain of Ser314 forming a hydrogen bond with the nitrogen atom of quinoline, which would impede the benzonitrile group binding. Therefore, we rationally designed the new chemotype of NSD2-PWWP1