title: Discovery and optimization of pyrrolo[1,2-a]pyrazinones leads to novel and selective inhibitors of PIM kinases.
abstract: A novel series of PIM inhibitors was derived from a combined effort in natural product-inspired library generation and screening. The novel pyrrolo[1,2-a]pyrazinones initial hits are inhibitors of PIM isoforms with IC50 values in the low micromolar range. The application of a rational optimization strategy, guided by the determination of the crystal structure of the complex in the kinase domain of PIM1 with compound 1, led to the discovery of compound 15a, which is a potent PIM kinases inhibitor exhibiting excellent selectivity against a large panel of kinases, representative of each family. The synthesis, structure-activity relationship studies, and pharmacokinetic data of compounds from this inhibitor class are presented herein. Furthermore, the cellular activities including inhibition of cell growth and modulation of downstream targets are also described.
authors.affiliation: Oncology, Nerviano Medical Sciences, viale Pasteur 10, 20014 Nerviano (MI), Italy. Electronic address: francesco.casuscelli@nervianoms.com.
authors.forename: Francesco
authors.initials: F
authors.lastname: Casuscelli
authors.forename: Elena
authors.initials: E
authors.lastname: Ardini
authors.forename: Nilla
authors.initials: N
authors.lastname: Avanzi
authors.forename: Elena
authors.initials: E
authors.lastname: Casale
authors.forename: Giovanni
authors.initials: G
authors.lastname: Cervi
authors.forename: Matteo
authors.initials: M
authors.lastname: D'Anello
authors.forename: Daniele
authors.initials: D
authors.lastname: Donati
authors.forename: Daniela
authors.initials: D
authors.lastname: Faiardi
authors.forename: Ronald D
authors.initials: RD
authors.lastname: Ferguson
authors.forename: Gianpaolo
authors.initials: G
authors.lastname: Fogliatto
authors.forename: Arturo
authors.initials: A
authors.lastname: Galvani
authors.forename: Aurelio
authors.initials: A
authors.lastname: Marsiglio
authors.forename: Danilo G
authors.initials: DG
authors.lastname: Mirizzi
authors.forename: Marisa
authors.initials: M
authors.lastname: Montemartini
authors.forename: Christian
authors.initials: C
authors.lastname: Orrenius
authors.forename: Gianluca
authors.initials: G
authors.lastname: Papeo
authors.forename: Claudia
authors.initials: C
authors.lastname: Piutti
authors.forename: Barbara
authors.initials: B
authors.lastname: Salom
authors.forename: Eduard R
authors.initials: ER
authors.lastname: Felder
mesh_terms: D055808:Drug Discovery; D006801:Humans; D062105:Molecular Docking Simulation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D051573:Proto-Oncogene Proteins c-pim-1; C406031:proto-oncogene proteins pim
keywords: Anti-cancer agents; Kinase selectivity; Natural product scaffold; PIM kinases; Pyrrolopyrazinone