title: Fragment-hopping-based discovery of a novel chemical series of proto-oncogene PIM-1 kinase inhibitors.
abstract: A new chemical series, triazolo[4,5-b]pyridines, has been identified as an inhibitor of PIM-1 by a chemotype hopping strategy based on a chemically feasible fragment database. In this case, structure-based virtual screening and in silico chemogenomics provide added value to the previously reported strategy of prioritizing among proposed novel scaffolds. Pairwise comparison between compound 3, recently discontinued from Phase I clinical trials, and molecule 8, bearing the selected novel scaffold, shows that the primary activities are similar (IC(50) in the 20 to 150 nM range). At the same time, some ADME properties (for example, an increase of more than 45% in metabolic stability in human liver microsomes) and the off-target selectivity (for example, an increase of more than 2 log units in IC(50)vs. FLT3) are improved, and the intellectual property (IP) position is enhanced. The discovery of a reliable starting point that fulfills critical criteria for a plausible medicinal chemistry project is demonstrated in this prospective study.
authors.affiliation: Experimental Therapeutics Program, Spanish National Cancer Research Centre (CNIO), C/Melchor Fernández Almagro 3, Madrid, Spain.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Saluste
authors.forename: Maria I
authors.initials: MI
authors.lastname: Albarran
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Alvarez
authors.forename: Obdulia
authors.initials: O
authors.lastname: Rabal
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Ortega
authors.forename: Carmen
authors.initials: C
authors.lastname: Blanco
authors.forename: Guido
authors.initials: G
authors.lastname: Kurz
authors.forename: Antonio
authors.initials: A
authors.lastname: Salgado
authors.forename: Paolo
authors.initials: P
authors.lastname: Pevarello
authors.forename: James R
authors.initials: JR
authors.lastname: Bischoff
authors.forename: Joaquin
authors.initials: J
authors.lastname: Pastor
authors.forename: Julen
authors.initials: J
authors.lastname: Oyarzabal
mesh_terms: D062313:Databases, Pharmaceutical; D055808:Drug Discovery; D006801:Humans; D020128:Inhibitory Concentration 50; D008862:Microsomes, Liver / Q000201:enzymology; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D000090063:Proto-Oncogene Mas; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors*
chemical_list: C000715470:MAS1 protein, human; D047428:Protein Kinase Inhibitors; D000090063:Proto-Oncogene Mas; C496634:PIM1 protein, human; D051573:Proto-Oncogene Proteins c-pim-1