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Inflammatory diseases: Big news on small molecules

James O’Connell, Research & Early Development
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James O’Connell, Research & Early Development
UCB has been a leader in biological therapies for inflammatory conditions, including rheumatoid arthritis. Now, our scientists have unveiled a discovery that could build on our small molecule heritage in medicinal chemistry – and open the door to a new wave of therapies for people with serious conditions.

TNF is a protein known to play a key role in inflammation. The development of biological therapies that block or inhibit TNF paved the way for a range of therapies that improved the lives of people with rheumatoid arthritis, axial spondyloarthritis, psoriatic arthritis, psoriasis.

Take rheumatoid arthritis, for example. UCB has played an important role in bringing monoclonal antibodies – which are a leading form of anti-TNF medication – to many patients around the world. By inhibiting TNF activity, inflammation can be significantly reduced. This eases patients’ symptoms and can spare them irreparable damage to their joints.

This was a major breakthrough for medical science in the late 20th century. For decades, researchers searched for ‘small molecules’ that could disrupt TNF activity and give patients the relief they needed. Despite the best efforts of the scientific community, it appeared that small molecules (pills) could not deliver the effect required. Monoclonal antibodies (injectables), which are much larger molecules, changed everything. 

However, the idea of small molecules that could affect TNF activity never went away. These elusive compounds were considered to be ‘high-hanging fruit’ in the scientific community, but there is good reason to pursue this Holy Grail.

Small molecules offer several advantages over larger biological therapies:, they can be taken orally which is convenient for patients, and they have shorter half-lives – which is beneficial to patients that need to stop taking their medication quickly.

They also have potential to cross the blood-brain barriers which could allow doctors to treat inflammatory diseases of the central nervous system. For example, inflammation may play a role in neurodegenerative conditions.

UCB was founded more than 90 years ago and made its mark in medical science by focusing on small molecules. Biological therapies are now a key component of our effort to improve the lives of patients, but our small molecule expertise remains. This experience and our active interest in autoimmune diseases inspired our scientists to explore new ways in which small molecules could influence TNF.

A new paper, published in Nature Communications by 16 current and former UCB scientists, unveils an important step forward in this quest. They describe the first ever genuine small molecule antagonist of TNF. This could be the beginning of another new chapter for people living with inflammatory diseases for which there are currently no oral anti-TNF medicines available.

For the first time we have been able to show that TNF-receptor interactions can be tackled with small molecules, not by taking on the interface where the partners interact, (which would be impossible), but by locking one of the partners in a signaling-incompetent state.  We discovered that TNF naturally moves and flips between different conformations all the time; some of these are biologically active, and some aren’t.  We took advantage of this understanding to design small chemical compounds which bind to these moving targets and restrict the movement to ensure clinically-desired outcomes.  It’s like using a grain of sand (small molecule) in the hinge of a door, rather than your arm (biologic), to stop it swinging.  This new thinking makes these targets druggable using medicinal chemistry that has been applied to targets such as enzymes for a hundred years.

We are delighted that a broad team effort has delivered this entirely new advance in medical science and hope to see this science translated into life-changing therapies for people in need.

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