ABSTRACT
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.
Subject(s)
Antineoplastic Agents/pharmacology , Azocines/pharmacology , Benzhydryl Compounds/pharmacology , Cyclohexanes/pharmacology , Dipeptides/pharmacology , Drug Discovery , Indoles/pharmacology , Pyrroles/pharmacology , Antineoplastic Agents/chemistry , Azocines/chemistry , Benzhydryl Compounds/chemistry , Cell Death/drug effects , Cell Proliferation/drug effects , Cyclohexanes/chemistry , Dipeptides/chemistry , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Indoles/chemistry , Jurkat Cells , Ligands , Molecular Structure , Pyrroles/chemistry , Structure-Activity RelationshipABSTRACT
Natural products represent compound classes with high chemical and structural diversity and various biological activities. Libraries based on natural products are valuable starting point in the search for novel biologically active substances. Here we report on the identification of the natural product podoverine A from the plant Podophyllum versipelle Hance as a novel tubulin-acting agent. A natural product compound collection was subjected to a high-content screen that monitors changes in cytoskeleton and DNA and podoverine A was identified as inhibitor of mitosis. This natural product causes mitotic arrest and inhibits microtubule polymerization in vitro and in cells by targeting the vinca binding site on tubulin.
