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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

  • Another Promising Target?

    Enzymes such as histone deacetylases (HDACs) or histone methyltransferases (HMTs) have for some time represented potentially druggable epigenetic targets. BioFocus discussed its work on HDAC inhibitors for treating Huntington disease.

    Roland Bürli, Ph.D., senior director scientific alliances at Biofocus, believes that a poly Q extension at the N-terminus of the huntingtin protein is thought to play a central role because the length of the poly Q repeat inversely correlates with Huntington disease onset.

    “Working with CHDI, a not-for-profit organization dedicated to finding therapies to treat Huntington disease, we have developed HDAC4 inhibitors and tested them in multiple biochemical and cell-based assays,” Dr. Bürli commented. “The most promising lead compounds are currently being scaled up for further studies in rodents.”

  • Current and Future Challenges

    As well as proving efficacy of epigenetic-derived small molecules, there are other technical and commercial barriers to successfully identifying and making progress with these types of drugs.

    One issue of working with epigenetic targets was identified by Gerard Drewes, Ph.D., vp of discovery research at Cellzome. According to Dr. Drewes, epigenetic processes are controlled by multiprotein complexes such as HDACs, and these complexes are difficult to recreate when using recombinant proteins in binding studies.

    “HDAC cell-based and biochemical assay data is not always consistent, as it can be difficult to assess the activity of a compound when using it on an isolated recombinant protein. Typically, recombinant proteins or enzymes don’t have the same conformation and activity as a protein in a protein complex. To overcome this problem, we developed a different technique using native proteins for the assay, which we call chemoproteomics.”

    The initial step in Cellzome’s approach is similar to affinity chromatography, in that it uses a bead matrix to capture different proteins, including many epigenetic enzymes, in their native form. Compounds are added to cells or tissue (either in vitro or in vivo), which then compete with the ligands of the bead matrix for binding of enzyme targets and their complexes. Subsequently, this competition is quantified using mass spectrometry, and a profile of target proteins is determined.

    Dr. Drewes’ data showed that when his group profiled a panel of 20 HDAC small molecule inhibitors including known HDAC inhibitor drugs such as SAHA (Zolinza/Merck & Co.) and romidepsin (Istodax/Celgene), IC50 curves for protein subunits could be measured and both known and novel protein targets identified.

    “We have established the utility of the chemoproteomics technology for HDAC inhibitors,” Dr. Drewes said. “The advantages of using this method is that it is quicker than the standard recombinant workflow and represents a highly multiplexed assay where the IC50 of a compound for 100 or more proteins can be measured in one run.

    “This is essentially an unbiased technology that allows the study of the ‘chemical space’ in which HDAC inhibitors operate, and it is this that will help us discover more novel protein targets.” Dr. Drewes also noted that the same technology is already being applied to other classes of epigenetic targets.

    Dr. Bountra highlighted a more far-reaching challenge, which has dogged the pharma industry and could hinder progress in epigenetic drug discovery. “All pharmas and biotechs are working on the same targets in parallel, in secret, so there is a massive duplication of effort.”

    “The tragedy of drug discovery attrition figures is that they are also duplicated and the outcomes are not shared. This means thousands of patients are exposed to molecules that many other groups definitely know are destined to fail in trials. That cannot be ethically or morally right. If we’re to make significant rapid progress with epigenetic drug discovery, this situation has to change.”

    According to Dr. Bountra, one problem is that early IP on molecules means information is not shared, which makes drug discovery slower, more difficult, and more expensive. The solution, he believes, is to establish public private partnerships such as the SGC, which includes academic collaborators in the U.K., U.S., Canada, and Sweden, alongside pharma companies such as GSK, Novartis, and Pfizer.

    These partnerships would take industry standard molecules for novel (“pioneer”) targets through to Phase II proof of clinical mechanism, without having any IP on the molecule. This would enable rapid publication of all data including negative clinical results, and would also de-risk the process, as novel targets would be clinically validated before large, parallel investments in multiple organizations.

    Dr. Bountra cited the epigenetic-derived molecule JQ1 as an example of how this could work. “JQ1 has been given freely to more than 100 labs worldwide, and is now being profiled in several therapy areas including inflammation, virology, and some forms of cancer.

    “The SGC has demonstrated that having the reagents freely available accelerates collaboration, and therefore science, and hence drug discovery. The impact of this one freely available molecule has been phenomenal—within 10 months this molecule has led to the initiation of proprietary programs, opened up a new area of science, enabled the establishment of a new biotech, and importantly, experts in pharma are trying to convert this target into a new drug for patients.”

    Overall, speakers were upbeat about the prospect of epigenetics being able to deliver. Dr. Kouzarides summarized, “We hope to soon see the first potent epigenetic-derived drugs in the clinic. Many of the initial inhibitor molecules such as I-BET and JQ1 may or may not work, but they will establish the principle that epigenetic-derived drugs can be selective and specific.

    “Novel druggable targets may be found in other chromatin modification pathways, so in the next few years we might see a shift away from kinase-based drug discovery and toward the epigenetic arena.”


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