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.

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    • "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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    ABSTRACT: Abstract Histone lysine methylation is a well-established transcriptional mechanism for the regulation of gene expression changes in eukaryotic cells and is now believed to function in neurons of the central nervous system to mediate the process of memory formation and behavior. In mature neurons, methylation of histone proteins can serve to both activate and repress gene transcription. This is in stark contrast to other epigenetic modifications, including histone acetylation and DNA methylation, which have largely been associated with one transcriptional state in the brain. In this review, we discuss the evidence for histone methylation mechanisms in the coordination of complex cognitive processes such as long-term memory formation and storage. In addition, we address the current literature highlighting the role of histone methylation in intellectual disability, addiction, schizophrenia, autism, depression, and neurodegeneration. Further, we discuss histone methylation within the context of other epigenetic modifications and the potential advantages of exploring this newly identified mechanism of cognition, emphasizing the possibility that this molecular process may provide an alternative locus for intervention in long-term psychopathologies that cannot be clearly linked to genes or environment alone.
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    • "However, these experiments revealed only a minor improvement of median survival for treated mice (vehicle: 29 d versus drug: 32 d; Daigle et al, 2011). A novel S-(5′-adenocyl)-L-homocysteine (SAM)-homologue (substance 4) was able to efficiently inhibit DOT1L – besides CARM1, PRMT1 and EHMT2 (Yao et al, 2011). However , further experiments are necessary to provide sufficient evidence for clinical studies in the future. "
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    ABSTRACT: The last three decades of cancer research were guided by the hypothesis that cancer cells evolve due to the accumulation of many genetic aberrations over time. While this is still true for most solid cancers, it might be different in haemato-malignant diseases, which are mostly characterized by chromosomal translocations that exhibit only few additional mutations. Some of the resulting fusion gene products functionally interfer with epigenetic mechanisms. Recent findings of mutated IDH1, IDH2, DNMT3A or TET2 in myelodysplastic syndrome/acute myeloid leukaemia patients underscore this notion, and point to the importance of epigenetic changes for developing tumour cells. This review aims (i) to give an overview about the different components of the epigenetic system, (ii) to describe the functions of different proteins or complexes that are involved in setting-up the epigenetic layer, (iii) to highlight some recent findings, and (iv) to describe the failures and successes when using drugs that are targeting epigenetic components.
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