5a7p › Citations

Docking and Linking of Fragments To Discover Jumonji Histone Demethylase Inhibitors.

Korczynska M, Le DD, Younger N, Gregori-Puigjané E, Tumber A, Krojer T, Velupillai S, Gileadi C, Nowak RP, Iwasa E, Pollock SB, Ortiz Torres I, Oppermann U, Shoichet BK, Fujimori DG
J Med Chem 59 1580-98 (2016)
Related entries: 5a7n, 5a7o, 5a7q, 5a7s, 5a7w, 5a80

Cited: 22 times
EuropePMC logo PMID: 26699912

Abstract

Development of tool molecules that inhibit Jumonji demethylases allows for the investigation of cancer-associated transcription. While scaffolds such as 2,4-pyridinedicarboxylic acid (2,4-PDCA) are potent inhibitors, they exhibit limited selectivity. To discover new inhibitors for the KDM4 demethylases, enzymes overexpressed in several cancers, we docked a library of 600,000 fragments into the high-resolution structure of KDM4A. Among the most interesting chemotypes were the 5-aminosalicylates, which docked in two distinct but overlapping orientations. Docking poses informed the design of covalently linked fragment compounds, which were further derivatized. This combined approach improved affinity by ∼ 3 log-orders to yield compound 35 (Ki = 43 nM). Several hybrid inhibitors were selective for KDM4C over the related enzymes FIH, KDM2A, and KDM6B while lacking selectivity against the KDM3 and KDM5 subfamilies. Cocrystal structures corroborated the docking predictions. This study extends the use of structure-based docking from fragment discovery to fragment linking optimization, yielding novel KDM4 inhibitors.

Articles - 5a7p mentioned but not cited (1)

  1. Docking and Linking of Fragments To Discover Jumonji Histone Demethylase Inhibitors. Korczynska M, Le DD, Younger N, Gregori-Puigjané E, Tumber A, Krojer T, Velupillai S, Gileadi C, Nowak RP, Iwasa E, Pollock SB, Ortiz Torres I, Oppermann U, Shoichet BK, Fujimori DG. J Med Chem 59 1580-1598 (2016)


Reviews citing this publication (7)

  1. Twenty years on: the impact of fragments on drug discovery. Erlanson DA, Fesik SW, Hubbard RE, Jahnke W, Jhoti H. Nat Rev Drug Discov 15 605-619 (2016)
  2. Inhibitors of Protein Methyltransferases and Demethylases. Kaniskan HÜ, Martini ML, Jin J. Chem Rev 118 989-1068 (2018)
  3. Application of Fragment-Based Drug Discovery to Versatile Targets. Li Q. Front Mol Biosci 7 180 (2020)
  4. 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)
  5. Computer-Aided Drug Design in Epigenetics. Lu W, Zhang R, Jiang H, Zhang H, Luo C. Front Chem 6 57 (2018)
  6. Histone Lysine Demethylase Inhibitors. Jambhekar A, Anastas JN, Shi Y. Cold Spring Harb Perspect Med 7 a026484 (2017)
  7. Recent Advances with KDM4 Inhibitors and Potential Applications. Wu Q, Young B, Wang Y, Davidoff AM, Rankovic Z, Yang J. J Med Chem 65 9564-9579 (2022)

Articles citing this publication (14)

  1. Structure-Based Discovery of a Selective KDM5A Inhibitor that Exhibits Anti-Cancer Activity via Inducing Cell Cycle Arrest and Senescence in Breast Cancer Cell Lines. Yang GJ, Ko CN, Zhong HJ, Leung CH, Ma DL. Cancers (Basel) 11 E92 (2019)
  2. Synthesis and Demonstration of the Biological Relevance of sp3 -rich Scaffolds Distantly Related to Natural Product Frameworks. Foley DJ, Craven PGE, Collins PM, Doveston RG, Aimon A, Talon R, Churcher I, von Delft F, Marsden SP, Nelson A. Chemistry 23 15227-15232 (2017)
  3. Small molecule KDM4s inhibitors as anti-cancer agents. Lin H, Li Q, Li Q, Zhu J, Gu K, Jiang X, Hu Q, Feng F, Qu W, Chen Y, Sun H. J Enzyme Inhib Med Chem 33 777-793 (2018)
  4. Impact of a Central Scaffold on the Binding Affinity of Fragment Pairs Isolated from DNA-Encoded Self-Assembling Chemical Libraries. Bigatti M, Dal Corso A, Vanetti S, Cazzamalli S, Rieder U, Scheuermann J, Neri D, Sladojevich F. ChemMedChem 12 1748-1752 (2017)
  5. In Silico Discovery of JMJD6 Inhibitors for Cancer Treatment. Ran T, Xiao R, Huang Q, Yuan H, Lu T, Liu W. ACS Med Chem Lett 10 1609-1613 (2019)
  6. A New Family of Jumonji C Domain-Containing KDM Inhibitors Inspired by Natural Product Purpurogallin. Souto JA, Sarno F, Nebbioso A, Papulino C, Álvarez R, Lombino J, Perricone U, Padova A, Altucci L, de Lera ÁR. Front Chem 8 312 (2020)
  7. Activation of Xist by an evolutionarily conserved function of KDM5C demethylase. Samanta MK, Gayen S, Harris C, Maclary E, Murata-Nakamura Y, Malcore RM, Porter RS, Garay PM, Vallianatos CN, Samollow PB, Iwase S, Kalantry S. Nat Commun 13 2602 (2022)
  8. Discovery of pyrazolo[1,5-a]pyrimidine-3-carbonitrile derivatives as a new class of histone lysine demethylase 4D (KDM4D) inhibitors. Fang Z, Wang TQ, Li H, Zhang G, Wu XA, Yang L, Peng YL, Zou J, Li LL, Xiang R, Yang SY. Bioorg Med Chem Lett 27 3201-3204 (2017)
  9. Structure-Based Screening of Tetrazolylhydrazide Inhibitors versus KDM4 Histone Demethylases. Małecki PH, Rüger N, Roatsch M, Krylova O, Link A, Jung M, Heinemann U, Weiss MS. ChemMedChem 14 1828-1839 (2019)
  10. Natural product myricetin is a pan-KDM4 inhibitor which with poly lactic-co-glycolic acid formulation effectively targets castration-resistant prostate cancer. Liu JS, Fang WK, Yang SM, Wu MC, Chen TJ, Chen CM, Lin TY, Liu KL, Wu CM, Chen YC, Chuu CP, Wang LY, Hsieh HP, Kung HJ, Wang WC. J Biomed Sci 29 29 (2022)
  11. Synthesis and Biological Evaluation of Tripartin, a Putative KDM4 Natural Product Inhibitor, and 1-Dichloromethylinden-1-ol Analogues. Guillade L, Sarno F, Tarhonskaya H, Nebbioso A, Alvarez S, Kawamura A, Schofield CJ, Altucci L, de Lera ÁR. ChemMedChem 13 1949-1956 (2018)
  12. Compounds and methods for inhibiting histone demethylases: a patent evaluation of US20160102096A1. Thaler F, Mercurio C. Expert Opin Ther Pat 26 1367-1370 (2016)
  13. Small Molecules Targeting the RNA-Binding Protein HuR Inhibit Tumor Growth in Xenografts. Wu X, Ramesh R, Wang J, Zheng Y, Armaly AM, Wei L, Xing M, Roy S, Lan L, Gao FP, Miao Y, Xu L, Aubé J. J Med Chem 66 2032-2053 (2023)
  14. Computational Prediction of the Binding Pose of Metal-Binding Pharmacophores. Karges J, Stokes RW, Cohen SM. ACS Med Chem Lett 13 428-435 (2022)


Quick links