From inflammation to remission: The promising role of jun kinase inhibitors in endometriosis

Jun kinase inhibitors show promise in resolving endometriosis pain and inflammation

Key Points

Highlights

• Dr. Stephen Palmer presented on the role of the immune system in endometriosis and the potential of JKIs to alleviate symptoms at the Annual International Medical Conference of the Endometriosis Foundation of America held in New York on April 1-2, 2023.
• The immune system's role in resolving pain and inflammation associated with endometriosis is addressed.
• Jun kinase inhibitors (JKI) can cause regression of endometriosis without affecting hormonal axes or normal uterine function.
• Cytokine levels produced by macrophages in endometriosis patients can be reduced with a JKI.

Importance

• Understanding the immune system's involvement in endometriosis could offer new strategies for managing pain and inflammation.
• Targeting Jun kinase enzymes provides a potential approach to alleviating endometriosis symptoms without interfering with hormonal functions.
• Developing more effective JKIs can improve treatment outcomes for endometriosis patients.

What's done here

• This speech is from Annual International Medical Conference of the Endometriosis Foundation of America held in New York on April 1-2, 2023, belongs to Dr. Stephen Palmer. 
• The immune system's role in resolving pain and inflammation associated with endometriosis is addressed.
• Target validation studies have been conducted on JKIs, demonstrating their efficacy in suppressing inflammation and reducing pain perception.
• A new JKI (CDD-2728) has been developed and tested in animal models, showing regression of endometriotic lesions.

Key results

• JKI treatment in a small study showed the elimination of pain perception in endometriosis patients.
• JKIs can suppress inflammatory cytokines produced by macrophages in endometriotic lesions.
• The new JNK inhibitor (CDD-2728) demonstrated effective inhibition of the target and regression of endometriotic lesions in animal models.
• The compound appeared safe and non-cytotoxic, showing promise for further development.
• The goal is to develop a diagnostic compound for the non-invasive identification of endometriosis and tracking treatment efficacy.

Lay Summary

Stephen Palmer from Baylor College of Medicine presented his speech at the Annual International Medical Conference of the Endometriosis Foundation of America held in New York on April 1-2, 2023. Dr. Palmer began his talk with a philosophy and a personal statement “Endometriosis is an inflammatory disease." He began by addressing the immune system as a way to resolve pain and inflammation associated with endometriosis.

Even though 90% of women experience retrograde menstruation, only 10-15% get endometriosis so there is something fundamentally different about the women who get endometriosis. There is an apparent overlap of the Jun kinase (JNK) target with IPF, osteoarthritis, inflammatory bowel disease, asthma, and endometriosis. They all share common pathologies associated with dysregulated inflammation.

He then went on to explain that they are targeting 3 enzymes that are part of the Jun kinase family: JNK 1-2 and 3. In the periphery, JNK1 and 2 are associated with inflammation and JNK3 is exquisitely expressed only in the CNS, it’s responsible for microglial activation, which is the macrophages in the CNS system that drive pain by interrupting JNK3 in the CNS, therefore they believe they are disrupting the pain signal.

He then gave information about the target validation that was done in the past for JNK inhibitors (JKIs).

JKIs can act to cause regression of endometriosis and not interfere with any of the hormonal axes that drive uterine function. In animals with lesions, JKI suppresses the inflammatory cytokines where the lesion is, with a very specific interruption of inflammation without affecting the normal operation of the uterus. He then talked about an unpublished bridging study that was performed on 20 patients which revealed that by week 12, the presence of the JKI had virtually eliminated the perception of pain in these patients, and that continued until week 20 and progestin appeared to be less effective.

It was previously proven that the cytokine levels produced by macrophages in the peritoneal fluid were elevated in patients with endometriosis and that with a JKI several of these cytokines in macrophages in cultures could be knocked down.

In pursuit of finding the next-generation JKI that targets aromatase regulation, RANTES, and NK cells, they wanted the new JK 123 inhibitor to block chemokine wind TGF beta and cytokine receptors that funnel through those JNK enzymes and regulate AP1 (Jun and Fos) as well as other JUN containing transcription factors. To be able to find this new JKI, they used DNA-encoded chemical libraries. They discovered that the JKI they are developing (CDD-2728) inhibits the target more effectively than the previous ones (CDD-939 and SP600125). They also found that primary human endometriotic lesion-derived stromal cells also responded to the new JKI similar to the epithelial cells. This particular compound caused regression of endometriotic lesions in an animal model of endometriosis. The compound appeared safe in terms of cytotoxicity.

He concluded by saying that they want a diagnostic compound that identifies patients with endometriosis with a non-invasive test, which could be utilized to track the efficacy of treatment modalities and identify that the patient is in remission from endometriosis.

Research Source: ​Leveraging the immune system to treat endometriosis - Stephen Palmer, PhD