Selective Inhibitors of Histone Methyltransferase DOT1L: Design, Synthesis, and Crystallographic Studies

Department of Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas 77030, USA.
Journal of the American Chemical Society (Impact Factor: 12.11). 09/2011; 133(42):16746-9. DOI: 10.1021/ja206312b
Source: PubMed


Histone H3-lysine79 (H3K79) methyltransferase DOT1L plays critical roles in normal cell differentiation as well as initiation of acute leukemia. We used structure- and mechanism-based design to discover several potent inhibitors of DOT1L with IC(50) values as low as 38 nM. These inhibitors exhibit only weak or no activities against four other representative histone lysine and arginine methyltransferases, G9a, SUV39H1, PRMT1 and CARM1. The X-ray crystal structure of a DOT1L-inhibitor complex reveals that the N6-methyl group of the inhibitor, located favorably in a predominantly hydrophobic cavity of DOT1L, provides the observed high selectivity. Structural analysis shows that it will disrupt at least one H-bond and/or have steric repulsion for other histone methyltransferases. These compounds represent novel chemical probes for biological function studies of DOT1L in health and disease.

    • "A conserved SET domain is characteristic of most lysine methyltransferases (KMTs) for histone proteins, although not all KMTs have a SET domain. Namely, the Dot1L family uses a catalytic mechanism distinct from SET domain containing enzymes such as G9a (Yao et al., 2011). Lysine demethylases (KDMs) are also separated into two categories: FAD-dependent amine oxidases such as LSD1 and Jumonji domain-containing KDMs such as JMJD1 (Hou and Yu, 2010; Krishnan et al., 2011). "
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