5LGT

Thieno[3,2-b]pyrrole-5-carboxamides as Novel Reversible Inhibitors of Histone Lysine Demethylase KDM1A/LSD1: Compound 15

Summary for 5LGT

• Entry DOI: 10.2210/pdb5lgt/pdb
• Descriptor: Lysine-specific histone demethylase 1A, REST corepressor 1, FLAVIN-ADENINE DINUCLEOTIDE, ... (4 entities in total)
• Functional Keywords: oxidoreductase
• Biological source: Homo sapiens (Human); More
• Cellular location: Nucleus : O60341 Q9UKL0
• Total number of polymer chains: 2
• Total formula weight: 102785.41

Authors

Mattevi, A.,Ciossani, G. (deposition date: 2016-07-08, 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

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: 28186757
DOI: 10.1021/acs.jmedchem.6b01019

Experimental method

X-RAY DIFFRACTION (3 Å)