DOT1L Inhibitor EPZ-5676 Displays Synergistic Antiproliferative Activity in Combination with Standard of Care Drugs and Hypomethylating Agents in MLL-Rearranged Leukemia Cells (original) (raw)
Research ArticleDrug Discovery and Translational Medicine
, Dorothy Iwanowicz, Danielle Johnston, Carly A. Campbell, Jesse J. Smith, Mikel P. Moyer, Robert A. Copeland, Edward J. Olhava, Margaret Porter Scott, Roy M. Pollock, Scott R. Daigle and Alejandra Raimondi
Journal of Pharmacology and Experimental Therapeutics September 2014, 350 (3) 646-656; DOI: https://doi.org/10.1124/jpet.114.214577
Abstract
EPZ-5676 [(2_R_,3_R_,4_S_,5_R_)-2-(6-amino-9_H_-purin-9-yl)-5-((((1_r_,3_S_)-3-(2-(5-(_tert_-butyl)-1_H_-benzo[_d_]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran-3,4-diol], a small-molecule inhibitor of the protein methyltransferase DOT1L, is currently under clinical investigation for acute leukemias bearing _MLL_-rearrangements (_MLL_-r). In this study, we evaluated EPZ-5676 in combination with standard of care (SOC) agents for acute leukemias as well as other chromatin-modifying drugs in cellular assays with three human acute leukemia cell lines: MOLM-13 (_MLL_-AF9), MV4-11 (_MLL_-AF4), and SKM-1 (non–_MLL_-r). Studies were performed to evaluate the antiproliferative effects of EPZ-5676 combinations in a cotreatment model in which the second agent was added simultaneously with EPZ-5676 at the beginning of the assay, or in a pretreatment model in which cells were incubated for several days in the presence of EPZ-5676 prior to the addition of the second agent. EPZ-5676 was found to act synergistically with the acute myeloid leukemia (AML) SOC agents cytarabine or daunorubicin in MOLM-13 and MV4-11 _MLL_-r cell lines. EPZ-5676 is selective for _MLL_-r cell lines as demonstrated by its lack of effect either alone or in combination in the nonrearranged SKM-1 cell line. In _MLL_-r cells, the combination benefit was observed even when EPZ-5676 was washed out prior to the addition of the chemotherapeutic agents, suggesting that EPZ-5676 sets up a durable, altered chromatin state that enhances the chemotherapeutic effects. Our evaluation of EPZ-5676 in conjunction with other chromatin-modifying drugs also revealed a consistent combination benefit, including synergy with DNA hypomethylating agents. These results indicate that EPZ-5676 is highly efficacious as a single agent and synergistically acts with other chemotherapeutics, including AML SOC drugs and DNA hypomethylating agents in _MLL_-r cells.
Footnotes
Received March 24, 2014.
Accepted July 2, 2014.
C.R.K. and D.I. contributed equally to this work.
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This article has supplemental material available at jpet.aspetjournals.org.Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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