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Thieno[3,2-b]pyrrole-5-carboxamides as New Reversible Inhibitors of Histone Lysine Demethylase KDM1A/LSD1. Part 2: Structure-Based Drug Design and Structure-Activity Relationship.

Vianello P, Sartori L, Amigoni F, Cappa A, Fagá G, Fattori R, Legnaghi E, Ciossani G, Mattevi A, Meroni G, Moretti L, Cecatiello V, Pasqualato S, Romussi A, Thaler F, Trifiró P, Villa M, Botrugno OA, Dessanti P, Minucci S, Vultaggio S, Zagarrí E, Varasi M, Mercurio C
J Med Chem 60 1693-1715 (2017)
Related entries: 5lgt, 5lgu, 5lhg, 5lhi

Cited: 19 times
EuropePMC logo PMID: 28186757

Abstract

The balance of methylation levels at histone H3 lysine 4 (H3K4) is regulated by KDM1A (LSD1). KDM1A is overexpressed in several tumor types, thus representing an emerging target for the development of novel cancer therapeutics. We have previously described ( Part 1, DOI 10.1021.acs.jmedchem.6b01018 ) the identification of thieno[3,2-b]pyrrole-5-carboxamides as novel reversible inhibitors of KDM1A, whose preliminary exploration resulted in compound 2 with biochemical IC50 = 160 nM. We now report the structure-guided optimization of this chemical series based on multiple ligand/KDM1A-CoRest cocrystal structures, which led to several extremely potent inhibitors. In particular, compounds 46, 49, and 50 showed single-digit nanomolar IC50 values for in vitro inhibition of KDM1A, with high selectivity in secondary assays. In THP-1 cells, these compounds transcriptionally affected the expression of genes regulated by KDM1A such as CD14, CD11b, and CD86. Moreover, 49 and 50 showed a remarkable anticlonogenic cell growth effect on MLL-AF9 human leukemia cells.

Articles - 5lhh mentioned but not cited (4)

  1. Crystal Structure of LSD1 in Complex with 4-[5-(Piperidin-4-ylmethoxy)-2-(p-tolyl)pyridin-3-yl]benzonitrile. Niwa H, Sato S, Hashimoto T, Matsuno K, Umehara T. Molecules 23 E1538 (2018)
  2. 3D-QSAR, molecular docking, and molecular dynamics simulation study of thieno[3,2-b]pyrrole-5-carboxamide derivatives as LSD1 inhibitors. Xu Y, He Z, Liu H, Chen Y, Gao Y, Zhang S, Wang M, Lu X, Wang C, Zhao Z, Liu Y, Zhao J, Yu Y, Yang M. RSC Adv 10 6927-6943 (2020)
  3. Discovery of new potent lysine specific histone demythelase-1 inhibitors (LSD-1) using structure based and ligand based molecular modelling and machine learning. Alabed SJ, Zihlif M, Taha M. RSC Adv 12 35873-35895 (2022)
  4. Pharmacological inhibition of LSD1 suppresses growth of hepatocellular carcinoma by inducing GADD45B. Sang N, Zhong X, Gou K, Liu H, Xu J, Zhou Y, Zhou X, Liu Y, Chen Z, Zhou Y, Li Y, Tao L, Su N, Zhou L, Qiu J, Yang X, Zuo Z, Fu L, Zhang J, Li D, Li C, Sun Q, Lei J, Li R, Yang S, Cen X, Zhao Y. MedComm (2020) 4 e269 (2023)


Reviews citing this publication (7)

  1. LSD1/KDM1A inhibitors in clinical trials: advances and prospects. Fang Y, Liao G, Yu B, Yu B. J Hematol Oncol 12 129 (2019)
  2. Advances toward LSD1 inhibitors for cancer therapy. Fu X, Zhang P, Yu B. Future Med Chem 9 1227-1242 (2017)
  3. Targeting histone methyltransferase and demethylase in acute myeloid leukemia therapy. Castelli G, Pelosi E, Testa U. Onco Targets Ther 11 131-155 (2018)
  4. Epigenetic drug discovery: a success story for cofactor interference. Ganesan A. Philos Trans R Soc Lond B Biol Sci 373 20170069 (2018)
  5. Histone lysine specific demethylase 1 inhibitors. Mehndiratta S, Liou JP. RSC Med Chem 11 969-981 (2020)
  6. Targeting Epigenetic Regulatory Enzymes for Cancer Therapeutics: Novel Small-Molecule Epidrug Development. Jin Y, Liu T, Luo H, Liu Y, Liu D. Front Oncol 12 848221 (2022)
  7. LSD1 inhibitors for cancer treatment: Focus on multi-target agents and compounds in clinical trials. Noce B, Di Bello E, Fioravanti R, Mai A. Front Pharmacol 14 1120911 (2023)

Articles citing this publication (8)



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