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Dec 1, 2011 (Vol. 31, No. 21)

Epigenetic-Derived Therapies on Horizon

Investigations Are Beginning to Elicit More Selective and Specific Druggable Targets

  • Click Image To Enlarge +
    Cellzome has developed a different kind of cell-based assay using native proteins.

    How is the current model of drug discovery faring? “It’s not working,” stated Chas Bountra, Ph.D., chief scientist at the Structural Genomics Consortium (SGC) and professor of translational medicine, University of Oxford. “There are too many targets to choose from, and many of the targets being worked on today will not deliver therapeutically because they are at too late a stage in the disease cascade.”

    Dr. Bountra was speaking at the recent “Epigenetics for Drug Discovery” conference, which was organized by Cellzome, CellCentric, and BioFocus, all companies with interests in the field of epigenetics.

    Tony Kouzarides, Ph.D., deputy director of the Gurdon Institute, University of Cambridge, agreed. “Much drug discovery has hinged on targeting kinases found in the cytoplasm. Perhaps by getting a crucial hit on a molecule in the nucleus, we might find better druggable targets.”

    Both speakers were suggesting that by studying the epigenetic information superimposed on the genome, such as modifications to the histone proteins that package DNA in chromatin, it may be possible to identify and more effectively block some of the cascades that cause disease states to occur.

  • A Safe BET?

    Click Image To Enlarge +
    Epigenetic action of I-BET inside the nucleus of MLL cells [University of Cambridge]

    One family of epigenetic-derived drug targets that dominated discussion at the conference were the BET (bromodomain and extra-terminal) proteins, a family of four proteins that selectively recognize and bind to acetylated lysine residues in histone. BET proteins stimulate transcription by recruiting specific types of proteins, for example the super elongation complex (SEC), to chromatin, leading to stimulation of transcriptional elongation of certain target genes including oncogenes and pro-inflammatory cytokines.

    As a consequence, targeting BET proteins and displacing them could provide a method of inducing cell cycle arrest and even cell death of defectively programmed cells. This is why inhibiting the action of BET proteins is being developed as an interesting strategy for treatment of cancer and inflammation.

    The BET proteins BRD4 and BRD3 have been implicated as part of the disease cascade for mixed lineage leukemia (MLL), an aggressive form of cancer that is hard to treat and mainly affects infants.

    “Proteomics evidence shows the SEC, and by inference MLL-fusions, are associated with BET proteins,” said Dr. Kouzarides. “Working with Cellzome and GlaxoSmithKline (GSK), we have characterized a small molecule we call I-BET 151 that interacts with BRD4 and BRD3 BET proteins and displaces them from genes regulated by MLL-fusions.”

    Dr. Kouzarides presented data to show that following treatment with I-BET 151 on two different human MLL-fusion cell lines (MV4;11 and MLL-AF9), there was a clear apoptotic effect seen, and transcription of key oncogenes BCL2, C-MYC, and CDK6 was repressed.

    Additionally, in animal models, mice transplanted with MV4;11 cells and treated with I-BET 151 survived without disease, and those transplanted with MV4;11 cells and not treated with I-BET 151 all died within 30–40 days. In a second animal model, mice transplanted with MLL-AF9 cells and treated with I-BET 151 all survived free of disease, and again the untreated mice died within 12–13 days.

    “We hope to progress I-BET 151 into clinical trials soon because we have shown that it kills leukemic cells in mice by displacing BET proteins from chromatin,” Dr. Kouzarides concluded. “Therefore, this has the potential to become the first potent and selective epigenetic drug.”

    NUT midline carcinoma is another form of cancer in which BET proteins have been implicated. Stefan Knapp, Ph.D., from the University of Oxford explained, “NUT midline carcinoma is a rare, aggressive human cancer in which most of the coding sequence of NUT is fused with the BET protein, BRD4 or BRD3.

    “In collaboration with the Dana Farber Cancer Institute, we have synthesized a small molecule based on available patent literature from Mitsubishi and GSK that we call JQ1, that selectively inhibits the BET protein BRD4.”

    Dr. Knapp presented data to show that following JQ1 treatment of mice with xenografts of cells from a patient’s NUT midline carcinoma chest tumor, apoptosis occurred and the tumor was reduced in weight and volume.

    “BET proteins are now becoming high profile as druggable targets,” Dr. Knapp summarized. “Around 20 percent of tumor cell lines respond well to BET inhibition, and there are many chemotypes we have identified that bind to BRD4, so there is plenty of opportunity to develop small molecule inhibitors.

    “Based on recent results on BET inhibition in cancer, a spin-off company from the Dana-Farber Institute, Tensha Therapeutics has already been set up to take JQ1 analogues into the clinic and has recently received initial funding of $15 million,” he added.

    Soren Beinke, Ph.D., investigator in the Epinova DPU at GSK, also presented on BET inhibition, showing that the I-BET small molecule could be used as an anti-inflammatory agent.

    Dr. Beinke’s group, along with a team at the Rockefeller Institute, demonstrated that I-BET suppressed the expression of key inflammatory mediators in macrophages. I-BET also prevented endotoxic shock in mice dosed with bacterial lipopolysaccharide, and attenuated bacterial induced sepsis.

    Most promisingly for therapeutic applications, a single dose of I-BET applied after lipopolysaccharide injection, at the time when mice started to develop symptoms of inflammatory disease, cured the mice. “I-BET could be a good candidate for the effective suppression of acute inflammatory conditions,” Dr. Beinke suggested.


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