Dual HKMT inhibitors

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Overview Many cancers show overexpression of histone methyl transferases and aberrant silencing of gene expression. While highly specific inhibitors of repressive histone methyltransferase EZH2 show clinical promise for tumours bearing mutant EZH2, they are far less effective in majority of tumours solely (over)expressing wild type EZH2. A team at Imperial College, utilising a powerful phenotypic screen, has developed a series of novel small molecules which target both HKMTs (EHMT2(G9a) and EZH2) for treatment of solid tumours.   Key features: Selective for a two key repressive HKMTs (EHMT2(G9a) and EZH2) while preserving others. Dual pharmacological inhibition of repressive HKMTs is highly effective in inducing changes in gene expression and inhibition of cell growth in breast and ovarian cancer cells expressing wild type EZH2. Reduces repressive chromatin marks while increasing permissive marks. Induces apoptosis in a breast, ovarian cancer, lymphoma cell lines at low uM to high nM concentrations. Synergistically increases drug sensitivity in combination studies with existing oncology drugs in various cancers (955 cancer cell lines tested). Tested in ovarian cancer xenograft model Development stage The team is currently exploring dual HKMT inhibitors utility in mono and combinational therapy. Intellectual property This technology is protected by patent applications in EU and USA.