EPZ5676

DOT1L is a non-SET domain containing methyltransferase whose function is important for the transcriptional activation of certain genes, DNA damage repair, and cell cycle regulation. DOT1L is known to play an essential role in MLL-rearranged leukemias, and thus has emerged as a drug target for these leukemias.^1,2 EPZ5676 is a highly potent aminonucleoside inhibitor of DOT1L histone methyltransferase activity (K_i = 80 pM) that demonstrates 37,000-fold selectivity over other methyltransferases.^3,4 In various human leukemia cell lines, EPZ5676 has been shown to inhibit the methylation of lysine 79 on histone 3 (IC₅₀s = 3-5 nM), decreasing MLL-fusion target gene expression (IC₅₀s = 53-67 nM).³ It can selectively inhibit the proliferation of acute leukemia cell lines bearing MLL translocations (IC₅₀s range from 3.5 nM - 1.3 µM).³ Continuous intravenous infusion of EPZ5676 at a dose of 35 mg/kg has been reported to cause complete and sustained tumor regression in a rat xenograft model of MLL-rearranged leukemia.³

WARNING This product is not for human or veterinary use.

1. Nguyen, A.T., He, J., Taranova, O., et al. Essential role of DOT1L in maintaining normal adult hematopoiesis. Cell Res. 21(9), 1370-1373 (2011).

2. Bernt, K.M., and Armstrong, S.A. A role for DOT1L in MLL-rearranged leukemias. Epigenomics 3(6), 667-670 (2011).

3. Daigle, S.R., Olhava, E.J., Therkelsen, C.A., et al. Potent inhibition of DOT1L as treatment of MLL-fusion leukemia. Blood 122(6), 1017-1025 (2013).

4. Basavapathruni, A., Olhava, E.J., Daigle, S.R., et al. Nonclinical pharmacokinetics and metabolism of EPZ-5676, a novel DOT1L histone methyltransferase inhibitor. Biopharm. Drug Dispos. 35(4), 237-252 (2014).