Language
English
Publication Date
8-25-2026
Journal
Proceedings of the National Academy of Sciences of the United States of America
DOI
10.1073/pnas.2607561123
PMID
42616792
PMCID
PMC13505988
PubMedCentral® Posted Date
8-19-2026
PubMedCentral® Full Text Version
Post-print
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.
Keywords
Female, Endometriosis, Humans, Animals, JNK Mitogen-Activated Protein Kinases, Protein Kinase Inhibitors, Mice, Pain
Published Open-Access
yes
Recommended Citation
Jimmidi, Ravikumar; Monsivais, Diana; Ta, Hai Minh; et al., "Identification of Potent Inhibitors of Jun N-Terminal Kinases for Treatment of Endometriosis and Associated Pain" (2026). Faculty, Staff and Students Publications. 3845.
https://digitalcommons.library.tmc.edu/baylor_docs/3845