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Structural Basis for KDM5A Histone Lysine Demethylase Inhibition by Diverse Compounds.

Horton JR, Liu X, Gale M, Wu L, Shanks JR, Zhang X, Webber PJ, Bell JSK, Kales SC, Mott BT, Rai G, Jansen DJ, Henderson MJ, Urban DJ, Hall MD, Simeonov A, Maloney DJ, Johns MA, Fu H, Jadhav A, Vertino PM, Yan Q, Cheng X
Cell Chem Biol 23 769-781 (2016)
Related entries: 5e6h, 5isl, 5ivb, 5ivc, 5ive, 5ivf, 5ivj, 5ivv, 5iw0, 5iwf

Cited: 45 times
EuropePMC logo PMID: 27427228

Abstract

The KDM5/JARID1 family of Fe(II)- and α-ketoglutarate-dependent demethylases removes methyl groups from methylated lysine 4 of histone H3. Accumulating evidence supports a role for KDM5 family members as oncogenic drivers. We compare the in vitro inhibitory properties and binding affinity of ten diverse compounds with all four family members, and present the crystal structures of the KDM5A-linked Jumonji domain in complex with eight of these inhibitors in the presence of Mn(II). All eight inhibitors structurally examined occupy the binding site of α-ketoglutarate, but differ in their specific binding interactions, including the number of ligands involved in metal coordination. We also observed inhibitor-induced conformational changes in KDM5A, particularly those residues involved in the binding of α-ketoglutarate, the anticipated peptide substrate, and intramolecular interactions. We discuss how particular chemical moieties contribute to inhibitor potency and suggest strategies that might be utilized in the successful design of selective and potent epigenetic inhibitors.

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  1. Structural Basis for KDM5A Histone Lysine Demethylase Inhibition by Diverse Compounds. Horton JR, Liu X, Gale M, Wu L, Shanks JR, Zhang X, Webber PJ, Bell JSK, Kales SC, Mott BT, Rai G, Jansen DJ, Henderson MJ, Urban DJ, Hall MD, Simeonov A, Maloney DJ, Johns MA, Fu H, Jadhav A, Vertino PM, Yan Q, Cheng X. Cell Chem Biol 23 769-781 (2016)


Reviews citing this publication (15)

  1. Inhibitors of Protein Methyltransferases and Demethylases. Kaniskan HÜ, Martini ML, Jin J. Chem Rev 118 989-1068 (2018)
  2. Histone H3 lysine K4 methylation and its role in learning and memory. Collins BE, Greer CB, Coleman BC, Sweatt JD. Epigenetics Chromatin 12 7 (2019)
  3. 2-Oxoglutarate-dependent dioxygenases in cancer. Losman JA, Koivunen P, Kaelin WG. Nat Rev Cancer 20 710-726 (2020)
  4. KDM5B is a master regulator of the H3K4-methylome in stem cells, development and cancer. Xhabija B, Kidder BL. Semin Cancer Biol 57 79-85 (2019)
  5. JARID1 Histone Demethylases: Emerging Targets in Cancer. Harmeyer KM, Facompre ND, Herlyn M, Basu D. Trends Cancer 3 713-725 (2017)
  6. KDM5 demethylases and their role in cancer cell chemoresistance. Plch J, Hrabeta J, Eckschlager T. Int J Cancer 144 221-231 (2019)
  7. The emerging role of KDM5A in human cancer. Yang GJ, Zhu MH, Lu XJ, Liu YJ, Lu JF, Leung CH, Ma DL, Chen J. J Hematol Oncol 14 30 (2021)
  8. Twenty years of menin: emerging opportunities for restoration of transcriptional regulation in MEN1. Dreijerink KMA, Timmers HTM, Brown M. Endocr Relat Cancer 24 T135-T145 (2017)
  9. Advances in Histone Demethylase KDM3A as a Cancer Therapeutic Target. Yoo J, Jeon YH, Cho HY, Lee SW, Kim GW, Lee DH, Kwon SH. Cancers (Basel) 12 E1098 (2020)
  10. Follicular lymphoma, a B cell malignancy addicted to epigenetic mutations. Korfi K, Ali S, Heward JA, Fitzgibbon J. Epigenetics 12 370-377 (2017)
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  12. JMJD family proteins in cancer and inflammation. Manni W, Jianxin X, Weiqi H, Siyuan C, Huashan S. Signal Transduct Target Ther 7 304 (2022)
  13. Histone methylation in pancreatic cancer and its clinical implications. Liu XY, Guo CH, Xi ZY, Xu XQ, Zhao QY, Li LS, Wang Y. World J Gastroenterol 27 6004-6024 (2021)
  14. Recent developments in catalysis and inhibition of the Jumonji histone demethylases. Sarah L, Fujimori DG. Curr Opin Struct Biol 83 102707 (2023)
  15. Epigenetic Factors as Etiological Agents, Diagnostic Markers, and Therapeutic Targets for Luminal Breast Cancer. Thang NX, Yoo S, La H, Lee H, Park C, Park KS, Hong K. Biomedicines 10 748 (2022)

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