Abstracts at Epigenetics Conference While we watch the price make a small drip drip today, let's be reminded of why we are all excited for Resverlogix first-in-class BET bromodomain inhibitors. Today and tomorrow at the 3rd Epigenetics in Drug Discovery, GSK and RVX are presenting on their inhibitors. Keep your eyes on the prize!
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https://www.gtcbio.com/component/conference/epigenetics-in-drug-discovery-agenda
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Today: The Effects of BET Protein Inhibition in Solid Tumor Models
Olena Barbash, Principal Investigator, Cancer Epigenetics, GlaxoSmithKline
The bromodomain and extra-terminal (BET) family of proteins, including Brd2, Brd3, Brd4, and BrdT, are chromatin reader proteins that bind acetylated lysines in the N-terminal tails of histones via their tandem bromodomains. We have developed a panel of selective inhibitors (I-BETs) that bind to BET proteins and disrupt their interaction with histones. BET inhibitors have been shown pre-clinically to possess anti-proliferative activity in multiple hematologic malignancies. Here we will describe the activity and sensitivity profile of GSK I-BET compounds in preclinical models of solid tumors.
Tomorrow: The Promise of BET Inhibitors for the Treatment of Disease: From Bench to Clinic
Peter R. Young, Senior Vice President, Discovery Research, Resverlogix
Increased synthesis of Apolipoprotein A-I (ApoA-I) and HDL provides a new approach to treating atherosclerosis through the stimulation of reverse cholesterol transport. RVX-208 is a small, orally bioavailable compound that increases the production of ApoA-I in hepatocytes in vitro, and in vivo in monkeys and humans, which results in increased HDL-C. RVX-208 is currently in Phase IIb clinical trials to test its ability to regress atherosclerosis. RVX-208 increases ApoA-I through a transcriptional mechanism that is mediated by inhibition of BET proteins, through binding to their bromodomains and competing with the natural acetylated lysine substrate found within specific peptide sequences at the amino terminus of certain histone proteins. RVX-208 shares the property of other BET inhibitors in its ability to inhibit the production of proinflammatory cytokine IL-6 in vitro. To explore this property of BET inhibitors further, we identified a second compound, RVX297, which inhibits both IL-6 and IL-17 production in vitro. Upon testing in vivo, RVX297 inhibits LPS induced cytokine production in mice, and has significant activity in two rodent models of autoimmune disease, multiple sclerosis and rheumatoid arthritis. These data suggest that BET inhibitors may have potential in multiple diseases, including atherosclerosis and autoimmune disease.
Benefits
1. Discovery of orally active BET inhibitors
2.Progress of BET inhibitors into clinical trials for atherosclerosis
3.Preclinical data supporting additional indications in autoimmune disease