title: 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.
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 IC50values 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.
authors.affiliation: Department of Experimental Oncology, Academic Drug Discovery, European Institute of Oncology , Via Adamello 16, 20139 Milano, Italy.
authors.forename: Paola
authors.identifier: 0000-0001-9100-2711
authors.initials: P
authors.lastname: Vianello
authors.affiliation: Department of Experimental Oncology, Academic Drug Discovery, European Institute of Oncology , Via Adamello 16, 20139 Milano, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Sartori
authors.affiliation: Department of Experimental Oncology, Academic Drug Discovery, European Institute of Oncology , Via Adamello 16, 20139 Milano, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Amigoni
authors.affiliation: Department of Experimental Oncology, Academic Drug Discovery, European Institute of Oncology , Via Adamello 16, 20139 Milano, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Cappa
authors.affiliation: Department of Experimental Oncology, Academic Drug Discovery, European Institute of Oncology , Via Adamello 16, 20139 Milano, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Fagá
authors.affiliation: Department of Experimental Oncology, Academic Drug Discovery, European Institute of Oncology , Via Adamello 16, 20139 Milano, Italy.
authors.forename: Raimondo
authors.initials: R
authors.lastname: Fattori
authors.affiliation: Department of Experimental Oncology, Academic Drug Discovery, European Institute of Oncology , Via Adamello 16, 20139 Milano, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Legnaghi
authors.affiliation: Department of Biology and Biotechnology, University of Pavia , Via Ferrata 1, 27100 Pavia, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Ciossani
authors.affiliation: Department of Biology and Biotechnology, University of Pavia , Via Ferrata 1, 27100 Pavia, Italy.
authors.forename: Andrea
authors.identifier: 0000-0002-9523-7128
authors.initials: A
authors.lastname: Mattevi
authors.affiliation: Department of Experimental Oncology, Academic Drug Discovery, European Institute of Oncology , Via Adamello 16, 20139 Milano, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Meroni
authors.affiliation: Department of Experimental Oncology, Academic Drug Discovery, European Institute of Oncology , Via Adamello 16, 20139 Milano, Italy.
authors.forename: Loris
authors.identifier: 0000-0002-9851-2965
authors.initials: L
authors.lastname: Moretti
authors.affiliation: Crystallography Unit, Department of Experimental Oncology, European Institute of Oncology , Via Adamello 16, 20139 Milano, Italy.|IFOM- The FIRC Institute of Molecular Oncology Foundation , Via Adamello 16, 20139 Milano, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Cecatiello
authors.affiliation: Crystallography Unit, Department of Experimental Oncology, European Institute of Oncology , Via Adamello 16, 20139 Milano, Italy.
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Pasqualato
authors.affiliation: Department of Experimental Oncology, Academic Drug Discovery, European Institute of Oncology , Via Adamello 16, 20139 Milano, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Romussi
authors.affiliation: Department of Experimental Oncology, Academic Drug Discovery, European Institute of Oncology , Via Adamello 16, 20139 Milano, Italy.
authors.forename: Florian
authors.initials: F
authors.lastname: Thaler
authors.affiliation: Department of Experimental Oncology, Academic Drug Discovery, European Institute of Oncology , Via Adamello 16, 20139 Milano, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Trifiró
authors.affiliation: Department of Experimental Oncology, Academic Drug Discovery, European Institute of Oncology , Via Adamello 16, 20139 Milano, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Villa
authors.affiliation: Department of Experimental Oncology, Academic Drug Discovery, European Institute of Oncology , Via Adamello 16, 20139 Milano, Italy.
authors.forename: Oronza A
authors.initials: OA
authors.lastname: Botrugno
authors.affiliation: Department of Experimental Oncology, Academic Drug Discovery, European Institute of Oncology , Via Adamello 16, 20139 Milano, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Dessanti
authors.affiliation: Department of Experimental Oncology, Academic Drug Discovery, European Institute of Oncology , Via Adamello 16, 20139 Milano, Italy.|Department of Biosciences, University of Milan , Via Celoria 26, 20133 Milano, Italy.
authors.forename: Saverio
authors.initials: S
authors.lastname: Minucci
authors.affiliation: Department of Experimental Oncology, Academic Drug Discovery, European Institute of Oncology , Via Adamello 16, 20139 Milano, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Vultaggio
authors.affiliation: Department of Experimental Oncology, Academic Drug Discovery, European Institute of Oncology , Via Adamello 16, 20139 Milano, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Zagarrí
authors.affiliation: Department of Experimental Oncology, Academic Drug Discovery, European Institute of Oncology , Via Adamello 16, 20139 Milano, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Varasi
authors.affiliation: Department of Experimental Oncology, Academic Drug Discovery, European Institute of Oncology , Via Adamello 16, 20139 Milano, Italy.|Genextra Group, DAC s.r.l. , Via Adamello 16, 20139 Milano, Italy.
authors.forename: Ciro
authors.initials: C
authors.lastname: Mercurio
mesh_terms: D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D031541:Fluorescence Resonance Energy Transfer; D057166:High-Throughput Screening Assays; D056466:Histone Demethylases; D006801:Humans; D020128:Inhibitory Concentration 50; D008239:Lysine / Q000737:chemistry*; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D011758:Pyrroles; D056466:Histone Demethylases; D008239:Lysine