Identification of potent inhibitors of JUN N-terminal kinases for treatment of endometriosis and associated pain

Madasu C, Tirupataiah Sirupangi, Genesis J Herrera, Herrera GJ, Kurt M Bohren, Kiran L Sharma, Zhi Tan, Tan Z, Hai Minh Ta, Fei Yuan, Yuan F, Murugesan Palaniappan, Caterina Clementi, Clementi C, Tang S, Suni Tang, Anna Catherine Unser, Jennifer Wilkinson, Robers MB, Matthew B Robers, Xiaoming Guan, Feng Li, Kim C, C. H. Kim, Choel Kim, Sankaran B, Banumathi Sankaran, Ramakrishna Kommagani, Kommagani R, Srinivas Chamakuri, Chamakuri S, Damian W Young, Young DW, Biem PY, Piraye Y Biem, Martin M. Matzuk, Stephen Palmer, Palmer SS, Stephen S Palmer, Diana Monsivais
Proceedings of the National Academy of Sciences of the United States of America · 2026 · vol. 123(34) , pp. e2607561123 · doi:10.1073/pnas.2607561123 · PMID:42616792 · W7203764199
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Abstract

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 (Kd = 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.

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MeSH descriptors

Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis JNK Mitogen-Activated Protein Kinases JNK Mitogen-Activated Protein Kinases JNK Mitogen-Activated Protein Kinases JNK Mitogen-Activated Protein Kinases JNK Mitogen-Activated Protein Kinases Pain Pain Pain Pain Protein Kinase Inhibitors Protein Kinase Inhibitors Protein Kinase Inhibitors Protein Kinase Inhibitors Protein Kinase Inhibitors Protein Kinase Inhibitors

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