12CV
Crystal Structure of human JNK1 Kinase Domain in complex with inhibitor CCD-2728
This is a non-PDB format compatible entry.
Summary for 12CV
| Entry DOI | 10.2210/pdb12cv/pdb |
| Descriptor | Mitogen-activated protein kinase 8, (4M)-N-[3-(dimethylcarbamoyl)-4-hydroxyphenyl]-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)-3H-1lambda~4~-benzothiophene-2-carboxamide (3 entities in total) |
| Functional Keywords | kinase, jnk1, mitogen-activated protein kinase 8, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 41834.44 |
| Authors | Ta, H.M.,Madasu, C.,Sirupangi, T.,Monsivais, D.,Matzuk, M.M.,Kim, C.,Palmer, S.S. (deposition date: 2026-03-27, release date: 2026-09-02) |
| Primary citation | Madasu, C.,Sirupangi, T.,Herrera, G.J.,Bohren, K.M.,Sharma, K.L.,Tan, Z.,Ta, H.M.,Yuan, F.,Palaniappan, M.,Clementi, C.,Tang, S.,Unser, A.C.,Wilkinson, J.,Robers, M.B.,Guan, X.,Li, F.,Kim, C.,Sankaran, B.,Kommagani, R.,Chamakuri, S.,Young, D.W.,Biem, P.Y.,Matzuk, M.M.,Palmer, S.S.,Monsivais, D. Identification of potent inhibitors of JUN N-terminal kinases for treatment of endometriosis and associated pain. Proc.Natl.Acad.Sci.USA, 123:e2607561123-e2607561123, 2026 Cited by PubMed 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 = 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. PubMed: 42616792DOI: 10.1073/pnas.2607561123 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.5 Å) |
Structure validation
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