Discovery of Novel, Potent, and Specific Cell-Death Inducers in the Jurkat Acute Lymphoblastic Leukemia Cell Line.
The limited clinical efficacy of many cancer therapeutics has initiated intense research efforts toward the discovery of novel chemical entities in this field. In this study, 31 hit candidates were selected from nearly 800,000 database compounds in a ligand-based virtual screening campaign. In turn, three of these hits were found to have (sub)micromolar potencies in proliferation assays with the Jurkat acute lymphatic leukemic cell line. In this assay, the three hits were found to exhibit higher potency than clinically tested cell-death inducers (GDC-0152, AT-406, and birinapant). Importantly, antiproliferative activity toward non-cancer peripheral blood mononuclear cells (PBMCs) was found to be marginal. Further biological characterization demonstrated the cell-death-inducing properties of these compounds. Biological testing of hit congeners excluded a nonspecific, toxic effect of the novel structures. Altogether, these findings may have profound relevance for the development of clinical candidates in tumor therapy.
Department of Chemistry, Biology, and Biotechnology, University of Perugia, Via Elce di Sotto 10, 06123 Perugia (Italy). emanuele@chemiome.chm.unipg.it.
Emanuele
E
Carosati
Department of Pathology, Medical Faculty, Heinrich-Heine-Universität, Universitätsstr. 1, 40225 Düsseldorf (Germany).
Natascha
N
van den Höfel
Department of Pathology, Medical Faculty, Heinrich-Heine-Universität, Universitätsstr. 1, 40225 Düsseldorf (Germany).
Manuela
M
Reif
Department of Chemistry, Biology, and Biotechnology, University of Perugia, Via Elce di Sotto 10, 06123 Perugia (Italy).
Giuseppe Marco
GM
Randazzo
Department of Pathology, Medical Faculty, Heinrich-Heine-Universität, Universitätsstr. 1, 40225 Düsseldorf (Germany).
Bettina
B
Stanitzki
Department of Pathology, Medical Faculty, Heinrich-Heine-Universität, Universitätsstr. 1, 40225 Düsseldorf (Germany).
Julia
J
Stevens
Department of Pathology, Medical Faculty, Heinrich-Heine-Universität, Universitätsstr. 1, 40225 Düsseldorf (Germany).
Helmut E
HE
Gabbert
Department of Chemistry, Biology, and Biotechnology, University of Perugia, Via Elce di Sotto 10, 06123 Perugia (Italy).
Gabriele
G
Cruciani
Molecular Drug Research Group, Medical Faculty, Heinrich-Heine-Universität, Universitätsstr. 1, 40225 Düsseldorf (Germany).
Raimund
R
Mannhold
Department of Pathology, Medical Faculty, Heinrich-Heine-Universität, Universitätsstr. 1, 40225 Düsseldorf (Germany). Mahotka@med.uni-duesseldorf.de.
Csaba
C
Mahotka
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001392:Azocines / Q000737:chemistry / Q000494:pharmacology*; D001559:Benzhydryl Compounds / Q000737:chemistry / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003510:Cyclohexanes / Q000737:chemistry / Q000494:pharmacology*; D004151:Dipeptides / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D019169:Jurkat Cells; D008024:Ligands; D015394:Molecular Structure; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D001392:Azocines; D001559:Benzhydryl Compounds; D003510:Cyclohexanes; D004151:Dipeptides; D007211:Indoles; D008024:Ligands; C559144:N-benzhydryl-5-(2-(methylamino)propanamido)-3-(3-methylbutanoyl)-6-oxodecahydropyrrolo(1,2-a)(1,5)diazocine-8-carboxamide; D011758:Pyrroles; C579046:GDC-0152; C582429:birinapant
FLAP; antitumor agents; apoptosis; cancer; virtual screening