title: Indolyl-pyrrolone as a new scaffold for Pim1 inhibitors.
abstract: Pim1 belongs to a family of serine/threonine kinases, which is involved in the control of cell growth, differentiation, and apoptosis. Pim1 plays a pivotal role in cytokine signaling and is implicated in the development of a large number of tumors, representing a very attractive target for anticancer therapy. In this work, we applied a virtual screening protocol aimed at identifying small molecules able to inhibit Pim1 activity. The search of novel inhibitors was performed through a structure-based molecular modeling approach, taking advantage of the availability of the three-dimensional crystal structure of inhibitors bound to Pim1. Starting from the knowledge of protein-ligand complexes, the software LigandScout was used to generate pharmacophoric models, in turn used as queries to perform a virtual screening of databases, followed by docking experiments. As a result, a restricted set of candidates for biological testing was identified. Finally, among the six compounds selected as potential inhibitors of Pim1, two candidates endowed with a significant activity against Pim1 emerged. Interestingly, one of these compounds has a chemical scaffold different from inhibitors previously identified.
authors.affiliation: Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Via Alcide de Gasperi 2, I-53100 Siena, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Olla
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Manetti
authors.forename: Emmanuele
authors.initials: E
authors.lastname: Crespan
authors.forename: Giovanni
authors.initials: G
authors.lastname: Maga
authors.forename: Adriano
authors.initials: A
authors.lastname: Angelucci
authors.forename: Silvia
authors.initials: S
authors.lastname: Schenone
authors.forename: Mauro
authors.initials: M
authors.lastname: Bologna
authors.forename: Maurizio
authors.initials: M
authors.lastname: Botta
mesh_terms: D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008024:Ligands; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D019311:Staurosporine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; C496634:PIM1 protein, human; D051573:Proto-Oncogene Proteins c-pim-1; D019311:Staurosporine