Inhibitors of human EZH2, and methods of use thereof

A method for treating cancer or myelodysplastic syndromes (MDS) in a subject having an increased level of trimethylated H3-K27 as a result of an EZH2 mutation in the substrate pocket domain of SEQ ID NO:

• 6, wherein SEQ ID NO:
• 6 comprises a mutation at amino acid position Y641 of EZH2 of SEQ ID NO:
• 1, wherein the mutation at amino acid position Y641 is selected from the group consisting of a substitution of phenylalanine (F) for the wild type residue tyrosine (Y) at amino acid position 641 of SEQ ID NO:
• 1 (Y641 F);
• a substitution of histidine (H) for the wild type residue tyrosine (Y) at amino acid position 641 of SEQ ID NO:
• 1 (Y641 H);
• a substitution of asparagine (N) for the wild type residue tyrosine (Y) at amino acid position 641 of SEQ ID NO:
• 1 (Y641 N);
• and a substitution of serine (S) for the wild type residue tyrosine (Y) at amino acid position 641 of SEQ ID NO:
• 1 (Y641 S);
• comprising administering to said subject a therapeutically effective amount of an EZH2 inhibitor, wherein the EZH2 inhibitor is
• or a pharmaceutically acceptable salt thereof.