Identification of potent inhibitors of JUN N-terminal kinases for treatment of endometriosis and associated pain
- Chandrashekhar Madasu
- Tirupataiah Sirupangi
- Genesis J. Herrera
- Kurt M. Bohren
- Kiran L. Sharma
- Zhi Tan
- Hai Minh Ta
- Fei Yuan
- Murugesan Palaniappan
- Caterina Clementi
- Suni Tang
- Anna Catherine Unser
- Jennifer Wilkinson
- Matthew B. Robers
- Xiaoming Guan
- Feng Li
- Choel Kim
- Banumathi Sankaran
- Ramakrishna Kommagani
- Srinivas Chamakuri
- Damian W. Young
- Piraye Y. Biem
- Martin M. Matzuk
- Stephen S. Palmer
- Diana Monsivais
2026-08-19
Endometriosis, defined as the ectopic growth of endometrial tissue outside of the uterine cavity, is an inflammatory and hormone-dependent disease that causes excruciating pelvic pain, infertility, and significantly decreases quality of life in affected patients. The JUN N-terminal kinases (JNKs) are a leading class of nonhormonal therapeutic targets that have been validated in preclinical models of endometriosis and in a Phase 1/2 clinical trial. Despite their therapeutic potential, JNK inhibitors with increased potency and specificity are needed to address the inflammatory pathology of endometriosis and to prevent disease progression. Leveraging a DNA-encoded chemical library collection of ~4 billion compounds, we identified lead inhibitor CDD-2428 and optimized derivatives, CDD-2728 and CDD-3013, with excellent binding affinity to JNK1-3 (K d = 0.12 to 3.7 nM), enhanced selectivity, metabolic stability, and cellular permeability. Crystallographic and biochemical studies confirmed that CDD-3013 exhibited superior kinase selectivity with improved efficacy compared to existing JNK inhibitors. In primary endometriosis cell models, CDD-2728 and CDD-3013 suppressed JNK-dependent inflammatory signaling, dampening pathways linked to pain, invasion, angiogenesis, and macrophage recruitment. In an endometriosis mouse model, both CDD-2728 and CDD-3013 reduced endometriotic lesion size, macrophage infiltration, and cellular proliferation, showing in vivo efficacy. When tested in a lipopolysaccharide-induced hyperalgesia model, CDD-2728 and CDD-3013 decreased markers of induced pain, as measured by changes in a dynamic weight bearing test and Grimace scores. These findings nominate CDD-2728 and CDD-3013 as potent, nonhormonal therapeutic candidates for endometriosis with broad anti-inflammatory and analgesic activity, addressing a critical unmet clinical need.