HDAC8

Researchers have been working to better understand what drives melanoma brain metastasis. They now report on the identification of a cell signaling pathway that regulates the metastatic spread of melanoma cells to the brain. Melanoma is the deadliest form of skin cancer because of its ability to quickly grow and spread throughout the body. More than half of those with advanced melanoma will see the disease spread to the brain, where it rapidly progresses, often leading to death in only three to four months. Researchers in Moffitt Cancer Center's Donald A. Adam Melanoma and Skin Cancer Center of Excellence have been working to better understand what drives melanoma brain metastasis. In a new study published in Nature Communications, they report on the identification of a cell signaling pathway that regulates the metastatic spread of melanoma cells to the brain. Melanoma tumors are composed of subgroups of cells with different gene expression patterns with varied abilities to invade surrounding tissues and survive anticancer treatments. It is unclear how these different melanoma subgroups contribute to tumor development and progression. In previous studies, Moffitt researchers determined that the protein HDAC8 regulated resistance to BRAF and MEK inhibitors commonly used to treat melanoma. HDAC8 removes chemical modifications called acetyl groups from other proteins, leading to alterations in gene expression patterns. The Moffitt team hypothesized that HDAC8 may also be involved in the regulation of gene expression patterns of melanoma cell subgroups. The researchers performed laboratory experiments and demonstrated that HDAC8 activity increased melanoma cell survival under stress conditions, including low oxygen, UV radiation, and BRAF/MEK inhibitor treatment. HDAC8 activity also changed the gene expression pattern of melanoma cells and caused the cells to develop characteristics associated with cell subgroups that were able to migrate into and invade surrounding sites. Their pre-clinical experiments found that increased HDAC8 expression and activity enhanced the ability of melanoma cells to metastasize to the brain, while no significant impact was observed in the number of metastatic tumors to other organs, such as the liver or lung. The researchers further investigated the molecular pathways of HDAC8-mediated brain metastasis and discovered that HDAC8 chemically modified the protein EP300, which subsequently caused cells to develop invasive characteristics. The researchers confirmed the importance of EP300 to melanoma brain metastases by showing that increased expression of EP300 decreased cell invasion and caused melanoma cells to be more sensitive to cell death. "These data show the importance of HDAC8 and EP300 activity to melanoma cell invasion to the brain and suggest that agents that target these pathways may inhibit brain metastasis," said Keiran Smalley, Ph.D., lead study author and director of Moffitt's Melanoma and Skin Cancer Center of Excellence. "Our work provides the first evidence that stress induced HDAC8 is a regulator of an invasive melanoma cell state that leads to increased brain metastasis." This study was supported by the National Institutes of Health (R01CA262483, R21CA267141, P30CA076292, P30CA247796) and by state appropriations provided in Florida Statute §381.915.

Isaac Hanson Francis deSouza was forced to step down as CEO following the company’s legal troubles. Photo: Victor J. Blue/Bloomberg via Getty Images US-based sequencing and diagnostics company Illumina reported in its Q2 filing that it is under investigation by the Securities and Exchange Commission (SEC) over its $8bn acquisition of Grail, the manufacturer of a proprietary multi-cancer early detection (MCED) test. This is the latest in a line of lawsuits faced by the firm over its decision. Grail began as a branch of Illumina and was then spun out as an independent start-up in 2016, though the parent retained a 12% stake. In 2020, Illumina opted to reacquire the company and announced a deal for $7.1bn. Recommended Reports Reports Histone Deacetylase 8 (Histone Deacetylase Like 1 or HDAC8 or EC 3.5.1.98) Drugs in Development b... GlobalData Reports Pharmaceuticals Industry Deals and Trends in April 2021 - Partnerships, Licensing, Investments, M... GlobalData View all The saga is long, complicated and neatly outlined here , but by June of this year Illumina had lost its CEO, been fined the maximum 10% of annual turnover by the EU (with an indication that a greater figure would have been sought if possible) and been ordered to divest Grail by the Federal Trade Commission (FTC). The issue at fault is twofold: at a base level Illumina stands accused of anticompetitive practices through the purchase, as the MCED test that Grail produces – and others like it by competitors – can only be processed by technology of which Illumina is the largest provider. The second problem is that, despite being told in July 2021 that the merger was under investigation by the European Commission, Illumina completed the deal a month later. The company has argued that its acquisition is a moral one that will accelerate the production of lifesaving tests and that it had to be completed within its initial deal period – ending in November 2021 – to avoid having to renegotiate, thereby slowing down the expansion. Regulators see it differently. The European Commission described the acquisition as “an unprecedented and very serious infringement undermining the effective functioning of the EU merger control system.” It found that the company had made a strategic decision to continue with the merger despite knowing it was possible it would be disallowed as the break-up fee for failing the takeover would outweigh the loss of profit from the divestment. This appears to be an accelerating trend in the medical field, following the news of UnitedHealth’s legal troubles . Legislation has not yet caught up to the "tidal wave" of mergers that the FTC reported in 2021, meaning investigations are either being suspended or cut short as regulators scramble to get on top. Companies may be taking advantage of this situation to pursue a more aggressive mergers and acquisitions (M&A) strategy than they would normally, knowing that the profits outweigh the costs of potential future fines. When companies beg forgiveness and not permission, there is a danger that anti-competitive practices will go unnoticed. Our signals coverage is powered by GlobalData’s Thematic Engine, which tags millions of data items across six alternative datasets - patents, jobs, deals, company filings, social media mentions and news — to themes, sectors and companies. These signals enhance our predictive capabilities, helping us to identify the most disruptive threats across each of the sectors we cover and the companies best placed to succeed.

RESEARCH TRIANGLE PARK, N.C., June 14, 2012 /PRNewswire/ -- TeraDiscoveries, Inc., announced today the identification of the first six biological targets for which the company is designing new drug candidates. This development follows the formation of a strategic relationship TeraDiscoveries has established with Microsoft Corp. Microsoft is providing support and cloud computing time on Windows Azure that TeraDiscoveries is applying to identify inhibitors of 25 top biological targets. The first six targets, which are now undergoing computer modeling, are HDAC8, JAK3, JAK2, PGP, HSP90, and the thioredoxin/glutathione reductase protein from the Schistosoma parasite. "We are developing a JAK3 kinase inhibitor that is selective against JAK1 and JAK2 enzymes and is indicated for rheumatoid arthritis treatment. We are also developing inhibitors for proteins with oncology indications, all of which are screened by sophisticated software for potential toxicology problems," says Ed Addison, CEO of TeraDiscoveries. One of TeraDiscoveries top inhibitors is for the thioredoxin/glutathione reductase protein associated with Schistosomiasis, also known as bilharzias. This is an orphan disease caused by parasitic worms that currently affects over 200 million people worldwide, mostly in developing countries. The newly described X-ray structure of the Schistosoma ssp. parasite will allow the design of much needed small molecule inhibitors to combat this disease. TeraDiscoveries uses its Inverse Design software that runs computational models to quickly scan virtual chemical libraries to find the strongest inhibitors of a specific biological target. The process identifies novel drug candidates that feature good clinical trial properties and demonstrate low probability of toxic side effects. Designing new drugs that bind to a specified protein target requires finding the best molecule in a vast chemical space. TeraDiscoveries' approach searches this space much more efficiently and cost-effectively than traditional methods. Companies can license molecules designed by TeraDiscoveries, or they can contract for services using Inverse Design running on Windows Azure to design, discover, or optimize new small molecule or peptide drugs for their targets. TeraDiscoveries also provides drug discovery and preclinical development services for companies seeking outside assistance. TeraDiscoveries will be presenting Inverse Design in the North Carolina Pavilion (booth 2935) at the 2012 BIO International Convention taking place June 18 to 21, 2012, in Boston. CEO Ed Addison will be delivering a 30-minute presentation on Inverse Design in the pavilion on Wednesday, June 20 at 2:30pm. About TeraDiscoveries, Inc. TeraDiscoveries is a drug discovery company located in Research Triangle Park, North Carolina. The company's Inverse Design software enables a paradigm shift to dramatically accelerate traditional drug discovery, simultaneously resulting in completely novel molecules. This proprietary software combined with cloud computing enables the rapid and accurate discovery of novel drug candidates to serve as a catalyst for improved health and well-being. Visit for information. All product and company names herein may be trademarks of their respective owners. SOURCE TeraDiscoveries, Inc.