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20 | SEPTEMBER 1, 2016 | GENengnews.com | Genetic Engineering & Biotechnology News Ceaseless flows of academic brainstorming and commercial innovation are reshaping old fields and creating new ones, ultimately spreading fertility to downstream disciplines such as epigenetics and epigenomics. When the genomic volcano blew, even the most far-sighted observers couldn't anticipate the impact the reinvigorated and entirely new fields of biology would have in clinical main- stream medicine and therapeutics. Moreover, epigenetic links to neuroscience, neuropsychol- ogy, physiology, and a dozen popular disciplines of investigation have since been discovered. In essence, In essence, genomic and epigenomic frontiers have been opened. They are now being ex- genomic In essence, genomic and epigenomic frontiers have been opened. They are now being ex- and epigenomic In essence, genomic and epigenomic frontiers have been opened. They are now being ex- frontiers have been opened. In essence, genomic and epigenomic frontiers have been opened. They are now being ex- They In essence, genomic and epigenomic frontiers have been opened. They are now being ex- are now being In essence, genomic and epigenomic frontiers have been opened. They are now being ex- ex- ploited by scientists determined to study the diversity of life func- tions, syndromes, traits, pre- dispositions, and behav- iors that contribute to health or wellness. At the forefront of the epigenetics field is a focus on the bromodomain and extra-terminal domain (BET) family of proteins that noncovalently and selectively bind with epigenetically modified (marked) amino acid residue sidechains on some histone protein subunits. Those histone protein subunits are found in chromatin. Winding around each histone is DNA, resulting in a compact nucleosome. When a suc- cession of nucleosomes are connected by linker DNA, the result is chromatin's "bead on a string" string" structure, which serves to compactly package DNA within the cell nucleus. In chro- structure, string" structure, which serves to compactly package DNA within the cell nucleus. In chro- which serves to compactly package DNA within the cell nucleus. In chro- matin, the nucleosome-bromodomain-binding steric interaction conformationally induces me-bromodomain-binding matin, the nucleosome-bromodomain-binding steric interaction conformationally induces steric interaction conformationally induces multiple regulatory transcription effects on the affected genes within the wound DNA. anscription multiple regulatory transcription effects on the affected genes within the wound DNA. effects on the affected genes within the wound DNA. Much evidence exists that rational, deliberate molecular interference or manipulation of sts Much evidence exists that rational, deliberate molecular interference or manipulation of that rational, deliberate molecular interference or manipulation of this nucleosome interaction is often a potent means to beneficially alter the transcription pat- ction is often a potent means to beneficially alter the transcription pat- tern of a disease or biological state of disorder. ological tern of a disease or biological state of disorder. state of disorder. Epigenetics-Focused Companies New dedicated enterprises were founded to explore and discover the clinical mani- ted New dedicated enterprises were founded to explore and discover the clinical mani- enterprises were founded to explore and discover the clinical mani- festations of the BET interactions. Key players in bromodomain epigenetics work, he festations of the BET interactions. Key players in bromodomain epigenetics work, BET interactions. Key players in bromodomain epigenetics work, especially as it relates to advanced clinical research, are Resverlogix and Zenith Epi- relates especially as it relates to advanced clinical research, are Resverlogix and Zenith Epi- to advanced clinical research, are Resverlogix and Zenith Epi- genetics. (The former company, which launched in 2001 with an objective of explor- ormer genetics. (The former company, which launched in 2001 with an objective of explor- company, which launched in 2001 with an objective of explor- ing cardiovascular disease, spun off the latter company in 2013). Both companies are ar ing cardiovascular disease, spun off the latter company in 2013). Both companies are disease, spun off the latter company in 2013). Both companies are dedicated almost exclusively to bromodomain epigenetic regulation or transcription in exclusively dedicated almost exclusively to bromodomain epigenetic regulation or transcription in to bromodomain epigenetic regulation or transcription in chromatin research. They have a diverse repertoire of candidate products, projects, and h. They have a diverse repertoire of candidate products, projects, and experimental and clinical knowledge. clinical experimental and clinical knowledge. knowledge. Resverlogix' current primary clinical candidate, RVX-208, now named apabetalone, rent Resverlogix' current primary clinical candidate, RVX-208, now named apabetalone, primary clinical candidate, RVX-208, now named apabetalone, is a selective bromodomain inhibitor for BRD4 at the BD2 site. It is in Phase III trials for domain is a selective bromodomain inhibitor for BRD4 at the BD2 site. It is in Phase III trials for inhibitor for BRD4 at the BD2 site. It is in Phase III trials for patients with cardiovascular disease and diabetes mellitus type 2, and it is the only epigenetic ascular patients with cardiovascular disease and diabetes mellitus type 2, and it is the only epigenetic disease and diabetes mellitus type 2, and it is the only epigenetic drug candidate having such status. g drug candidate having such status. such status. Zenith Epigenetics is devoted to oncology clinical research and has a bromodomain in- ics Zenith Epigenetics is devoted to oncology clinical research and has a bromodomain in- is devoted to oncology clinical research and has a bromodomain in- hibitor, ZEN-3694, in a Phase I trial for a form of intractable metastatic prostate cancer 4, hibitor, ZEN-3694, in a Phase I trial for a form of intractable metastatic prostate cancer in a Phase I trial for a form of intractable metastatic prostate cancer (mCRPC). There are several renowned collaborating investigators and groups involved, are several renowned collaborating investigators and groups involved, including Eric Small, M.D., chief of the division of hematology and oncology at the Uni- mall, including Eric Small, M.D., chief of the division of hematology and oncology at the Uni- M.D., chief of the division of hematology and oncology at the Uni- versity of California, San Francisco, and Howard Scher, M.D., chief of the genitourinary nia, versity of California, San Francisco, and Howard Scher, M.D., chief of the genitourinary San Francisco, and Howard Scher, M.D., chief of the genitourinary oncology service at Memorial Sloan Kettering Cancer Center. Memorial Sloan Kettering Cancer Center. The inhibitor binds to two bromodomain sites, BD1 and BD2, with relatively good binds The inhibitor binds to two bromodomain sites, BD1 and BD2, with relatively good to two bromodomain sites, BD1 and BD2, with relatively good affinity at submicromolar K cromolar affinity at submicromolar K K D resulting in a potent beneficial effect by upregulating cer- tain tumor suppression gene programs. It also downregulates super-enhancer orchestra- ession tain tumor suppression gene programs. It also downregulates super-enhancer orchestra- gene programs. It also downregulates super-enhancer orchestra- tion of several genes that are involved in transcriptions that promote pathogenesis al tion of several genes that are involved in transcriptions that promote pathogenesis genes that are involved in transcriptions that promote pathogenesis is numerous hematological and solid tumor malignancies. Moreover, the drug rous is numerous hematological and solid tumor malignancies. Moreover, the drug hematological and solid tumor malignancies. Moreover, the drug candidate appears to work in a synergistic manner with standard-of-care date candidate appears to work in a synergistic manner with standard-of-care appears to work in a synergistic manner with standard-of-care chemo- and immunotherapy. o- chemo- and immunotherapy. and immunotherapy. Eric Campeau, Ph.D., is director of biology at Zenith Epigenetics. With c Eric Campeau, Ph.D., is director of biology at Zenith Epigenetics. With Campeau, Ph.D., is director of biology at Zenith Epigenetics. With reference to the Phase I study, regarding any transcriptomic and proteomic nce reference to the Phase I study, regarding any transcriptomic and proteomic to the Phase I study, regarding any transcriptomic and proteomic profile analysis of patients, he noted that the study involves subtype variations e profile analysis of patients, he noted that the study involves subtype variations analysis of patients, he noted that the study involves subtype variations for therapeutic optimization. The first patient was dosed in June of this year. erapeutic for therapeutic optimization. The first patient was dosed in June of this year. optimization. The first patient was dosed in June of this year. Donald J. McCaffrey, co-founding president and CEO of both compa- nald Donald J. McCaffrey, co-founding president and CEO of both compa- J. McCaffrey, co-founding president and CEO of both compa- nies, said that the firms were succeeding because they were not only adept aid that the firms were succeeding because they were not only adept at clinical research but also capable of unraveling biological complexities. nical at clinical research but also capable of unraveling biological complexities. research but also capable of unraveling biological complexities. While many other firms may have a single discovery platform, he main- many other firms may have a single discovery platform, he main- Awaken Dormant DNA, Epigenetically See Epigenetics on page 22 DNA associates with histone proteins to form chromatin. By Zephyris at the English language Wikipedia, CC BY-SA 3.0, BY-SA 3.0 https://commons.wikimedia. org/w/index.php?curid=6998210 Rob Ranulph Jones At first, it was just a premonitory tremor: the piecing together of a rudimentary whole human genome in 2001. Then, just two years later, came an earth-shaking eruption: the completion of the Human Genome Project. This explosive event rocked the molecular genetics landscape and released bioscientific forces that to this day show no signs of abating. OMICS