Science Breakthrough: Novel BD2-Selective BET Inhibitor Shows Promise for Arthritis and Inflammatory Diseases

May 12, 2020 /BioValleyBIOON / — Researchers from the Peter MacCallum Cancer Centre have discovered an innovative method to suppress severe inflammation in mice, paving the way for treating inflammatory conditions and certain cancers such as arthritis, psoriasis, liver disease, and some types of cancer.AutoimmunityThe treatment of the disease provides a potential new approach.

This study was conducted by Professor Mark Dawson's laboratory andGlaxoSmithKline(GSK) scientists collaborated on the study, during which they identified the aforementioned issue while seeking new methods to improve an existing anticancer therapy. The current anticancer therapy interferes with the process that controls gene expression within cells.

In cancer andAutoimmunityIn certain diseases, specific genes in overactive cells are often expressed at abnormally high levels, and these genes are the cause of the disease. Therapies that can reverse this abnormal gene expression have benefits in both cancer and inflammation.

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However, because these processes are also essential in normal cells, many of these treatments have side effects, prompting researchers to modify drug design and thereby develop compounds that are more specific than previous therapies.

Dr. Omer Gilan, the lead author of the study, said, "The findings were truly surprising. To advance the research,"GlaxoSmithKline"Our medicinal chemistry team initially designed these new series of compounds in an attempt to improve existing cancer treatments. We did not initially focus on inflammation."

The research team was studying a drug that inhibits the activity of BET family proteins—such drugs are currently being tested in various cancer trials around the world.Clinical Trial。

These drugs function by blocking two sites in BET proteins, rendering the proteins nonfunctional and killing cancer cells.

Although this treatment may be effective, it can also lead to some unnecessary side effects.

The researchers sought to determine whether they could minimize off-target effects while maintaining anticancer activity. To achieve this, they collaborated with a team of scientists from GlaxoSmithKline PLC., who designed compounds capable of interfering with only one site at a time.

To their surprise, they found that when they selectively blocked the second BD2 site, the drug no longer exhibited anticancer activity but instead became an effective inhibitor of immune cell function.

Dr. Gilan said, "When selective BD2 receptor blockers are administered to subjects with human-likeAutoimmunity"In mice with inflammatory conditions (including arthritis, psoriasis, and liver disease), it effectively suppressed immune function."

Mice tolerated this therapy well, with significant improvement in their inflammatory diseases; in some cases, it was even more effective than currently available treatments.

"Another significant finding of this study is that we have finally unraveled a biological mystery: why these BET proteins have two nearly identical domains throughout evolution. Importantly, by revealing that each domain has completely distinct and non-redundant functions, we have identified a novel approach to tackling diseases such as cancer and inflammation," explained Professor Mark Dawson, the corresponding author of the study.

If confirmed in humans, this finding will have significant implications for patients with malignant and inflammatory diseases in Australia and around the world.

Professor Dawson stated, "There is still a long way to go before testing this new therapy in humans, but the evidence from proof-of-concept studies in mice is certainly promising."

The paper titled "Selective targeting of BD1 and BD2 of the BET proteins in cancer and immune-inflammation" was published in Science. (Bioon.com)

References:

Omer Gilan et al. Selective targeting of BD1 and BD2 of the BET proteins in cancer and immuno-inflammation， Science (2020). DOI： 10.1126/science.aaz8455