Biological Activity of EPZ004777

EPZ004777 is a potent, selective DOT1L inhibitor with IC50 of 0.4 nM.
IC50 value: 0.4 nM [1]
Target: DOT1L
in vitro: EPZ004777 selectively inhibits cellular H3K79 methylation and inhibits expression of key MLL fusion target genes. Following DOT1L inhibition, EPZ004777 selectively inhibits proliferation of MLL-Rearranged cell lines and MLL-AF9-transformed murine hematopoietic cells. In addition, EPZ004777 also induces differentiation and apoptosis in MLL-rearranged cells [1]. EPZ004777 selectively inhibits proliferation of MLL–AF10 and CALM–AF10-transformed murine bone marrow cells [2]. DOT1L inhibition by EPZ004777 results in significantly decreased proliferation, decreased expression of MLL-AF6 target genes, and cell cycle arrest of MLL-AF6-transformed cells [3].
in vivo: EPZ004777 produces potent antitumor efficacy, and significantly increases median survival in a mouse xenograft model of MLL leukemia [1].

Clinical Information of EPZ004777

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References on EPZ004777

[1]. Daigle SR, et al. Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor. Cancer Cell. 2011 Jul 12;20(1):53-65.
[2]. Chen L, et al. Abrogation of MLL-AF10 and CALM-AF10-mediated transformation through genetic inactivation or pharmacological inhibition of the H3K79 methyltransferase Dot1l. Leukemia. 2013 Apr;27(4):813-22.
[3]. Deshpande AJ, et al. Leukemic transformation by the MLL-AF6 fusion oncogene requires the H3K79 methyltransferase Dot1l. Blood. 2013 Mar 28;121(13):2533-41.