**Thanks to Dr. Liye Zhang, a Postdoc Fellow in the Computational Biomedicine department at Boston University School of Medicine for attending this meeting for us and providing a nice summary.
The 14th Annual Discovery on TARGET conference (Sep 19th to Sep 22th 2016 held in Westin Boston Waterfront, Boston, MA) was centered on novel drug discovery against various hot targets, including epigenetic readers and modifiers. The talks covered a wide variety of topics, from mechanistic studies on epigenetic regulation to novel chemistry for drug discovery, optimization and development.
Most of epigenetic drugs are developed against cancer; there was also few talks covering novel application of epigenetic drugs in other diseases including neurological diseases and cardiovascular diseases. Here I am going to highlight a few talks that may be of general interest.
Entiostat Development: Targeting Immune Suppress Cells to Expand Utility of Immune Checkpoint inhibitors
Peter Ordentlich | Syndax Pharmaceuticals, Boston, MA, USA
Peter’s talk highlights the potential of combining HDAC inhibitor entiostat with cancer immune therapy to further improve the response rate of cancer immune therapy. He shows evidence from mouse experiments and clinical trials that entiostat can specifically decrease the population of Myeloid-derived suppressor cells (MDSCs) or Regulatory T cells (Tregs), both of which suppress the activities of cytotoxic T cells. However, the mechanism is still largely unknown and may be an interesting and important topic to explore.
Gregory Verdine | Erving Professor, Harvard University, Boston, MA, USA
Gregory started by explaining that the biological (such as monoclonal antibody, limited to proteins outside of cell) and small molecules (require hydrophobic pocket) can only target about 20% of human proteome. Therefore, cell-penetrating mini-proteins, which combine the ability to target large region of biological molecules and cell-penetrating properties of small molecules, will be crucial for future drug development to target the currently 80% un-druggable proteins.
He described the first stapled peptide that entered into clinical trials for cancer patients and another example of cell-penetrating mini-proteins SAMH1 that can target Notch transcription factor, which is generally considered as un-druggable targets(Nat Protoc. 2011 Jun;6(6):761-71. doi: 10.1038/nprot.2011.324.).
Lastly, he described the new chemistry to generate the second generation stapled peptides and even methods to produce orally available small peptide drug (http://www.fogpharma.com/). This talk is not centered on epigenetics, however, I believe this type of peptide can serve as a unique toolbox and even open new opportunities for researchers in the epigenetic fields.
Targeting BET Protein Degradation for New Cancer Therapeutics
Shaomeng Wang | Professor, University of Michigan, MI, USA
Shaomeng showed extensive results that the bromodomain degrader drug, which takes advantage of a method called Protacs to target protein for ubiquitination and then degradation, is very potent and specific in degrading the BET proteins (Proc. Natl. Acad. Sci. USA, 98 (2001), pp. 8554–8559 and Chemistry&Biology 22(6), 2015, 755–763).
RNA-Seq analysis showed that the effect of a BET inhibitor and degrader in transcriptome is quite distinct: very few genes were upregulated by BET degrader, while huge number of genes were upregulated by BET inhibitor treatment. In addition, the degrader induced a much higher level of apoptosis compared with the BET inhibitors. Surprisingly, based on the mouse model, such a potent drug is also well tolerated. His results highlighted the potential of a protein degrader drug compared with the traditional inhibitor drug, especially considering that degrader drug does not need continuous administration as inhibitor drug.
Mechanism-Based Combination Strategies for BET inhibitors in Solid and Hematologic Cancer
Anastasia Wyce | Investigator, GlaxoSmithLine, UK
Anastasia showed interesting results that the Pan-BET inhibitors sensitize the cancer cells to chemotherapy, more specifically to the inhibitors to PI3K pathways. In fact, such sensitization effect even persists in BET inhibition resistant cell lines after the BET inhibitors treatment is stopped. This shows the potential of a combination therapy of drug targeting epigenetic component and traditional treatment option.
Further elucidation of this poorly-understood mechanism may not only provide insights into rationally designed cancer combination therapy in the future, but also shed light on novel biology into the cellular circuit related to epigenetic regulation.
BET Bromodomain Inhibitors in Prostate Cancer
Irfan Asangani | Assistant Professor, University of Pennsylvania, USA
Irfan focused on understanding the potential of targeting bromodomain family protein to repress Androgen Receptor (AR) signaling in prostate cancer. He showed that cell lines with intact/elevated AR signaling are sensitive to BET inhibitor JQ1. Such sensitivity is likely to be mediated by the abolished AR recruitment to its binding sites (showed by ChIP-Seq) and thus reduced expression of AR downstream genes.
Xenograft model also indicated that BET inhibitor is also effective in castration-resistance prostate tumors, where the resistant form of AR (AR-V7) is also inhibited. As a result, multiple clinical trials are ongoing to evaluate BET inhibitors as alternative/combinatory drug to treat advanced prostate cancer. Given the importance of bromodomain proteins in multiple signaling pathways, many more such stories are likely to show up in other tumor types.