5LHH
Structure of the KDM1A/CoREST complex with the inhibitor 4-ethyl-N-[3-(methoxymethyl)-2-[[4-[[(3R)-pyrrolidin-3-yl]methoxy]phenoxy]methyl]phenyl]thieno[3,2-b]pyrrole-5-carboxamide
Summary for 5LHH
| Entry DOI | 10.2210/pdb5lhh/pdb |
| Descriptor | Lysine-specific histone demethylase 1A, REST corepressor 1, FLAVIN-ADENINE DINUCLEOTIDE, ... (6 entities in total) |
| Functional Keywords | histone demethylase, inhibitor, complex, oxidoreductase |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 2 |
| Total formula weight | 147971.18 |
| Authors | Cecatiello, V.,Pasqualato, S. (deposition date: 2016-07-11, release date: 2017-02-22, Last modification date: 2024-01-10) |
| Primary citation | Vianello, P.,Sartori, L.,Amigoni, F.,Cappa, A.,Faga, G.,Fattori, R.,Legnaghi, E.,Ciossani, G.,Mattevi, A.,Meroni, G.,Moretti, L.,Cecatiello, V.,Pasqualato, S.,Romussi, A.,Thaler, F.,Trifiro, P.,Villa, M.,Botrugno, O.A.,Dessanti, P.,Minucci, S.,Vultaggio, S.,Zagarri, E.,Varasi, M.,Mercurio, C. 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. J. Med. Chem., 60:1693-1715, 2017 Cited by PubMed 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 IC = 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 IC 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. PubMed: 28186757DOI: 10.1021/acs.jmedchem.6b01019 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.05 Å) |
Structure validation
Download full validation report
