DOE OSTI · 3685152
Identification of potent inhibitors of JUN N-terminal kinases for treatment of endometriosis and associated pain
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 (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.
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Madasu, Chandrashekhar [Department of Pathology and Immunology, Baylor College of Medicine; Center for Drug Discovery, Baylor College of Medicine] (ORCID:0000000221529689), Sirupangi, Tirupataiah [Department of Pathology and Immunology, Baylor College of Medicine; Center for Drug Discovery, Baylor College of Medicine] (ORCID:0009000231908540), Herrera, Genesis J. [Department of Pathology and Immunology, Baylor College of Medicine; Center for Drug Discovery, Baylor College of Medicine], Bohren, Kurt M. [Department of Pathology and Immunology, Baylor College of Medicine; Center for Drug Discovery, Baylor College of Medicine] (ORCID:0000000231834118), Sharma, Kiran L. [Department of Pathology and Immunology, Baylor College of Medicine; Center for Drug Discovery, Baylor College of Medicine] (ORCID:000000021988389X), Tan, Zhi [Department of Pathology and Immunology, Baylor College of Medicine; Center for Drug Discovery, Baylor College of Medicine], Ta, Hai Minh [Verna and Marrs McLean, Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine] (ORCID:0000000272986177), Yuan, Fei [Department of Pathology and Immunology, Baylor College of Medicine; Center for Drug Discovery, Baylor College of Medicine], Palaniappan, Murugesan [Department of Pathology and Immunology, Baylor College of Medicine; Center for Drug Discovery, Baylor College of Medicine] (ORCID:0000000349166565), Clementi, Caterina [Celmatix Therapeutics], Tang, Suni [Department of Pathology and Immunology, Baylor College of Medicine; Center for Drug Discovery, Baylor College of Medicine], Unser, Anna Catherine [Department of Pathology and Immunology, Baylor College of Medicine; Center for Drug Discovery, Baylor College of Medicine] (ORCID:0009000146781469), Wilkinson, Jennifer [Promega Corporation] (ORCID:000900021994715X), Robers, Matthew B. [Promega Corporation], Guan, Xiaoming [Department of Obstetrics and Gynecology, Baylor College of Medicine] (ORCID:0000000227444512), Li, Feng [Department of Pathology and Immunology, Baylor College of Medicine; Center for Drug Discovery, Baylor College of Medicine] (ORCID:0000000296804614), Kim, Choel [Center for Drug Discovery, Baylor College of Medicine; Verna and Marrs McLean, Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine], Sankaran, Banumathi [Molecular Biophysics and Integrated Bioimaging, Berkeley Center for Structural Biology, Lawrence Berkeley National Laboratory], Kommagani, Ramakrishna [Department of Pathology and Immunology, Baylor College of Medicine; Center for Drug Discovery, Baylor College of Medicine], Chamakuri, Srinivas [Department of Pathology and Immunology, Baylor College of Medicine; Center for Drug Discovery, Baylor College of Medicine], Young, Damian W. [Department of Pathology and Immunology, Baylor College of Medicine; Center for Drug Discovery, Baylor College of Medicine], Biem, Piraye Y. [Celmatix Therapeutics], Matzuk, Martin M. [Department of Pathology and Immunology, Baylor College of Medicine; Center for Drug Discovery, Baylor College of Medicine] (ORCID:0000000214458632), Palmer, Stephen S. [Department of Pathology and Immunology, Baylor College of Medicine; Center for Drug Discovery, Baylor College of Medicine; Celmatix Therapeutics], Monsivais, Diana [Department of Pathology and Immunology, Baylor College of Medicine; Center for Drug Discovery, Baylor College of Medicine] (ORCID:0000000156606392). 2026-08-19. Identification of potent inhibitors of JUN N-terminal kinases for treatment of endometriosis and associated pain. https://doi.org/10.1073/pnas.2607561123
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