7JM5

Crystal structure of KDM4B in complex with QC6352

Summary for 7JM5

• Entry DOI: 10.2210/pdb7jm5/pdb
• Descriptor: Lysine-specific demethylase 4B, NICKEL (II) ION, 3-[({(1R)-6-[methyl(phenyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl}methyl)amino]pyridine-4-carboxylic acid, ... (5 entities in total)
• Functional Keywords: kdm4, kdm4b, protein-inhibitor complex, demethylase, epigenetics, oxidoreductase-inhibitor complex, oxidoreductase, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 85377.59

Authors

White, S.W.,Yun, M. (deposition date: 2020-07-31, release date: 2022-02-02, Last modification date: 2024-11-20)

Primary citation

Singh, S.,Abu-Zaid, A.,Jin, H.,Fang, J.,Wu, Q.,Wang, T.,Feng, H.,Quarni, W.,Shao, Y.,Maxham, L.,Abdolvahabi, A.,Yun, M.K.,Vaithiyalingam, S.,Tan, H.,Bowling, J.,Honnell, V.,Young, B.,Guo, Y.,Bajpai, R.,Pruett-Miller, S.M.,Grosveld, G.C.,Hatley, M.,Xu, B.,Fan, Y.,Wu, G.,Chen, E.Y.,Chen, T.,Lewis, P.W.,Rankovic, Z.,Li, Y.,Murphy, A.J.,Easton, J.,Peng, J.,Chen, X.,Wang, R.,White, S.W.,Davidoff, A.M.,Yang, J.
Targeting KDM4 for treating PAX3-FOXO1-driven alveolar rhabdomyosarcoma.
Sci Transl Med, 14:eabq2096-eabq2096, 2022

PubMed Abstract: Chimeric transcription factors drive lineage-specific oncogenesis but are notoriously difficult to target. Alveolar rhabdomyosarcoma (RMS) is an aggressive childhood soft tissue sarcoma transformed by the pathognomonic Paired Box 3-Forkhead Box O1 (PAX3-FOXO1) fusion protein, which governs a core regulatory circuitry transcription factor network. Here, we show that the histone lysine demethylase 4B (KDM4B) is a therapeutic vulnerability for PAX3-FOXO1 RMS. Genetic and pharmacologic inhibition of KDM4B substantially delayed tumor growth. Suppression of KDM4 proteins inhibited the expression of core oncogenic transcription factors and caused epigenetic alterations of PAX3-FOXO1-governed superenhancers. Combining KDM4 inhibition with cytotoxic chemotherapy led to tumor regression in preclinical PAX3-FOXO1 RMS subcutaneous xenograft models. In summary, we identified a targetable mechanism required for maintenance of the PAX3-FOXO1-related transcription factor network, which may translate to a therapeutic approach for fusion-positive RMS.

PubMed: 35857643
DOI: 10.1126/scitranslmed.abq2096

Experimental method

X-RAY DIFFRACTION (2.7 Å)