The lysine methyltransferase EZH2 (KMT6), part of the polycomb repressive complex 2, catalyzes trimethylation of lysine 27 on histone H3 (H3K27me3) and is involved in proliferation and aggressive cell growth associated with neoplastic cells. CPI-169 is a selective EZH2 inhibitor with IC50 values of 0.24, 0.51, and 6.1 nM for wild-type EZH2, Y641N mutant EZH2, and wild-type EZH1, respectively. It decreases cellular levels of H3K27me3 (EC50 = 70 nM), triggering cell cycle arrest and ultimately resulting in apoptosis in a large panel of non-Hodgkin’s lymphoma (NHL) cell lines. With subcutaneous administration of 200 mg/kg/twice a day, CPI-169 was shown to inhibit tumor growth in a NHL xenograft model, reducing global H3K27me3. It has also been shown to synergize with the B-cell lymphoma 2 inhibitor, ABT-199 , to suppress the growth of NHL cell lines.
