EPZ004777   

GtoPdb Ligand ID: 7377

Synonyms: EPZ 004777 | EPZ-004777
Compound class: Synthetic organic
Comment: EPZ004777 is an analogue of the enzyme co-factor S-adenosyl methionine (SAM). SAM is the classical methyl donor for methyltrasferases.
2D Structure
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Physico-chemical Properties
Hydrogen bond acceptors 10
Hydrogen bond donors 5
Rotatable bonds 12
Topological polar surface area 150.79
Molecular weight 539.32
XLogP 3.34
No. Lipinski's rules broken 0
SMILES / InChI / InChIKey
Canonical SMILES O=C(Nc1ccc(cc1)C(C)(C)C)NCCCN(C(C)C)CC1OC(C(C1O)O)n1ccc2c1ncnc2N
Isomeric SMILES O=C(Nc1ccc(cc1)C(C)(C)C)NCCCN(C(C)C)C[C@H]1O[C@H]([C@@H]([C@@H]1O)O)n1ccc2c1ncnc2N
InChI InChI=1S/C28H41N7O4/c1-17(2)34(13-6-12-30-27(38)33-19-9-7-18(8-10-19)28(3,4)5)15-21-22(36)23(37)26(39-21)35-14-11-20-24(29)31-16-32-25(20)35/h7-11,14,16-17,21-23,26,36-37H,6,12-13,15H2,1-5H3,(H2,29,31,32)(H2,30,33,38)/t21-,22-,23-,26-/m1/s1
InChI Key WXRGFPHDRFQODR-ICLZECGLSA-N
No information available.
Mechanism Of Action and Pharmacodynamic Effects
EPZ004777 inhibits histone methylation (at H379K) by DOT1L. The histone lysine methyltransferase DOT1L has been shown to be involved in the development and maintenance of MLL-rearranged leukemias [1]; rearrangement of the MLL gene and abberant methylation of lysine 79 of histone H3 are associated with some leukemias [1,3]. Treatment with EPZ004777 causes cell death and tumour regression in cell and animal models containing MLL rearrangements [2]. EPZ004777 is >1000-fold selective for DOT1L compared to other histone lysine methyltransferases tested [2].