Protein lysine methyltransferases are important regulators of epigenetic signaling. These enzymes catalyze the transfer of donor methyl groups from S-adenosylmethionine to specific acceptor lysines on histones, leading to changes in chromatin structure and transcriptional regulation. These enzymes also methylate nonhistone protein substrates, revealing an additional mechanism to regulate cellular physiology. The oncogenic protein SMYD2 represses the functional activities of the tumor suppressor proteins p53 and Rb, making it an attractive drug target. Here we report the discovery of AZ505, a potent and selective inhibitor of SMYD2 that was identified from a high throughput chemical screen. We also present the crystal structures of SMYD2 with p53 substrate and product peptides, and notably, in complex with AZ505. This substrate competitive inhibitor is bound in the peptide binding groove of SMYD2. These results have implications for the development of SMYD2 inhibitors, and indicate the potential for developing novel therapies targeting this target class.
Glial growth factor 2 (GGF2) is a neuronal signal that promotes the proliferation and survival of the oligodendrocyte, the myelinating cell of the central nervous system (CNS). The present study examined whether recombinant human GGF2 (rhGGF2) could effect clinical recovery and repair to damaged myelin in chronic relapsing experimental autoimmune encephalomyelitis (EAE) in the mouse, a major animal model for the human demyelinating disease, multiple sclerosis. Mice with EAE were treated with rhGGF2 during both the acute and relapsing phases. Clinically, GGF2 treatment delayed signs, decreased severity, and resulted in statistically significant reductions in relapse rate. rhGGF2-treated groups displayed CNS lesions with more remyelination than in controls. This correlated with increased mRNA expression of myelin basic protein exon 2, a marker for remyelination, and with an increase in the CNS of the regulatory cytokine, interleukin 10, at both the RNA and protein levels. Thus, a beneficial effect of a neurotrophic growth factor has been demonstrated on the clinical, pathologic, and molecular manifestations of autoimmune demyelination, an effect that was associated with increased expression of a T helper 2 cytokine. rhGGF2 treatment may represent a novel approach to the treatment of multiple sclerosis.Most therapeutic strategies in the human demyelinating disease, multiple sclerosis (MS), have been based on modulating the immune response, and the animal model of MS, experimental autoimmune encephalomyelitis (EAE), has been particularly useful for testing potential therapeutic agents (1, 2). EAE, a CD4 ϩ T helper 1 (Th1) T cell-mediated disease of the central nervous system (CNS), involves autosensitization to myelin antigens and in the SJL mouse is a chronic relapsing neurologic disease with inflammatory demyelinated CNS lesions highly reminiscent of MS (3-5). Relatively unexplored in demyelinating conditions has been the therapeutic potential of neurotrophic factors with known regulatory effects on the myelinating cell. Prominent among these factors are members of the neuregulin family of soluble and transmembrane proteins belonging to the epidermal growth factor superfamily (6). Recombinant human glial growth factor 2 (rhGGF2) is a secreted isoform of neuregulin with documented stimulatory effects on oligodendrocytes and Schwann cells (7-10). Because oligodendrocytes are a major target in the MS lesion and because remyelination occurs in MS and EAE (3,4), it was hypothesized that administration of rhGGF2 to animals with EAE might ameliorate the disease. This report presents the findings from a large series of experiments in which rhGGF2 was given to mice at different stages of adoptively transferred chronic relapsing EAE. The results have shown that not only does rhGGF2 have marked beneficial effects at the acute and relapsing phases of the disease but it is also associated with structural and molecular evidence for enhanced remyelination of CNS lesions in long-term rhGGF2-treated animals.
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