What Makes the Immune System Compromise Your Health?

Janus kinase (JAK) enzymes can be responsible for inappropriate activation of immune cells that play a critical role in autoimmune disorders.

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Imagine that one day your immune system, which has always cared for you, suddenly becomes a foe, causing you pain.

That’s exactly what happens to someone with an autoimmune disease like rheumatoid arthritis (RA). The immune system initiates and propagates the creation of cells that attack one’s own body, causing inflammation and pain, particularly in the hands, wrists and feet.

Janus kinase (JAK) enzymes play a critical role in the body by transmitting messages from the outside to the inside of cells. In the immune system, these JAK-dependent messages are essential to fight infection but a malfunction can also play a role in the generation of autoimmune disease.1

“Patients with RA have autoreactive immune cells, which means the cells turn against their body,” explains Lisa Olson, vice president, immunology research, AbbVie. “In these cells, JAK enzymes transmit signals that leads to the immune system’s attack on their own joints.”
 

Stopping unhealthy signaling

With a greater understanding of the role JAK enzymes play in autoimmune diseases, researchers examined ways to stop the unhealthy JAK signaling by creating inhibitors that interrupt the transmission of these faulty signals.
 
“JAK inhibitors are a special class of small molecules that lower JAK enzyme activity,” says Neil Wishart, discovery co-leader, research and development, AbbVie.

Back in the mid-1990s, JAK inhibitors were first studied to help prevent rejection of kidneys after transplant surgery. They were shown to control signaling of interleukin-2, a key pathway that is over stimulated in the rejection of a transplanted kidney.2

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Diagram of similar crystal structures of JAK 1 (blue) and JAK 2 (green).3,4

Pursuing selectivity

First generation JAK inhibitors were brought to market beginning in 2011 with different degrees of selectivity.1

“We believed that developing a second-generation JAK inhibitor to treat RA patients was possible,” Olson says. “We committed to creating something unique, a molecule with more selectivity.”

A cross-functional team effort was critical for the identification of a new, more selective JAK inhibitor. “It took many months of long hours, creative thinking and cutting-edge science to bring ideas to reality,” Wishart adds.
 
An early molecule contender became a candidate to test in humans but after careful evaluation, it was found to not be viable for humans and researchers had to go back to generating hundreds of new molecules.
 
“We’re constantly balancing the excitement of new discoveries with a tolerance for things going wrong,” Olson says. “It was never a question of if we should give up; it was about what else do we have to work with and how can we move forward.”
 
Wishart adds, “We had underlying confidence in our approach, and the knowledge and expertise to create a better molecule. The organization backed us, which allowed us to make courageous and rapid decisions.”

This long journey is not yet completed; researchers continue to work toward a therapeutic option that may one day help patients. 

“The effort that it takes to shepherd a molecule through the discovery and development process is amazing. The team has demonstrated unwavering focus every step of the way to ensure we maximize the impact for patients” Olson says. “It’s a long but rewarding journey that we look forward to completing; our motivation is to make this possibility real.”

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1. Gadina M. Janus Kinases: An Ideal Target for the Treatment of Autoimmune Diseases. Journal of Investigative Dermatology Symposium Proceedings (2013) 16,S70-S72.
2. Changelian1 P, Flanagan M, Ball D, Douglas J. Ball, et al. Prevention of Organ Allograft Rejection by a Specific Janus Kinese 3 Inhibitor. Science 31 Oct 2003; Vol. 302, Issue 5646, pp. 875-878.
3. Friedman M, Frank KE, Aguirre A, Argiriadi MA, Davis H, Edmunds JJ, et al. Structure activity optimization of 6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-1]pyrazines as Jak1 kinase inhibitors. Bioorg Med Chem Lett 2015:25:4399-404.
4. Lucet IS, Fantino E, Styles M, Bamert R, Patel O, Broughton SE, et al. The structural basis of Janus kinase 2 inhibition by a potent and specific pan-Janus kinase inhibitor. Blood 2006:107:176-83.