title: Generation of tricyclic imidazo[1,2-a]pyrazines as novel PI3K inhibitors by application of a conformational restriction strategy.
abstract: The involvement of the phosphoinositide 3-kinases (PI3Ks) in several diseases, especially in the oncology area, has singled it as one of the most explored therapeutic targets in the last two decades. Many different inhibitor classes have been developed by the industry and academia with a diverse selectivity profile within the PI3K family. In the present manuscript we report a further exploration of our lead PI3K inhibitor ETP-46321 (Martínez González et al., 2012)1by the application of a conformational restriction strategy. For that purpose we have successfully synthesized novel tricyclic imidazo[1,2-a]pyrazine derivatives as PI3K inhibitors. This new class of compounds had enable the exploration of the solvent-accessible region within PI3K and resulted in the identification of molecule 8q with the best selectivity PI3Kα/δ isoform profile in vitro, and promising in vivo PK data.
authors.affiliation: Experimental Therapeutics Programme, Spanish National Cancer Research Centre (CNIO), C/Melchor Fernández Almagro 3, E-28029 Madrid, Spain.
authors.forename: Sonia
authors.initials: S
authors.lastname: Martínez González
authors.affiliation: Experimental Therapeutics Programme, Spanish National Cancer Research Centre (CNIO), C/Melchor Fernández Almagro 3, E-28029 Madrid, Spain.
authors.forename: Sonsoles
authors.initials: S
authors.lastname: Rodríguez-Arístegui
authors.affiliation: Experimental Therapeutics Programme, Spanish National Cancer Research Centre (CNIO), C/Melchor Fernández Almagro 3, E-28029 Madrid, Spain.
authors.forename: Ana Isabel
authors.initials: AI
authors.lastname: Hernández
authors.affiliation: Experimental Therapeutics Programme, Spanish National Cancer Research Centre (CNIO), C/Melchor Fernández Almagro 3, E-28029 Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Varela
authors.affiliation: Experimental Therapeutics Programme, Spanish National Cancer Research Centre (CNIO), C/Melchor Fernández Almagro 3, E-28029 Madrid, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: González Cantalapiedra
authors.affiliation: Experimental Therapeutics Programme, Spanish National Cancer Research Centre (CNIO), C/Melchor Fernández Almagro 3, E-28029 Madrid, Spain.
authors.forename: Rosa María
authors.initials: RM
authors.lastname: Álvarez
authors.affiliation: Experimental Therapeutics Programme, Spanish National Cancer Research Centre (CNIO), C/Melchor Fernández Almagro 3, E-28029 Madrid, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Rodríguez Hergueta
authors.affiliation: Experimental Therapeutics Programme, Spanish National Cancer Research Centre (CNIO), C/Melchor Fernández Almagro 3, E-28029 Madrid, Spain.
authors.forename: James R
authors.initials: JR
authors.lastname: Bischoff
authors.affiliation: Experimental Therapeutics Programme, Spanish National Cancer Research Centre (CNIO), C/Melchor Fernández Almagro 3, E-28029 Madrid, Spain.
authors.forename: María Isabel
authors.initials: MI
authors.lastname: Albarrán
authors.affiliation: Experimental Therapeutics Programme, Spanish National Cancer Research Centre (CNIO), C/Melchor Fernández Almagro 3, E-28029 Madrid, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Cebriá
authors.affiliation: Experimental Therapeutics Programme, Spanish National Cancer Research Centre (CNIO), C/Melchor Fernández Almagro 3, E-28029 Madrid, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Cendón
authors.affiliation: Experimental Therapeutics Programme, Spanish National Cancer Research Centre (CNIO), C/Melchor Fernández Almagro 3, E-28029 Madrid, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Cebrián
authors.affiliation: Experimental Therapeutics Programme, Spanish National Cancer Research Centre (CNIO), C/Melchor Fernández Almagro 3, E-28029 Madrid, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Alfonso
authors.affiliation: Experimental Therapeutics Programme, Spanish National Cancer Research Centre (CNIO), C/Melchor Fernández Almagro 3, E-28029 Madrid, Spain. Electronic address: jpastor@cnio.es.
authors.forename: Joaquín
authors.initials: J
authors.lastname: Pastor
mesh_terms: D000818:Animals; D006207:Half-Life; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D020128:Inhibitory Concentration 50; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship
chemical_list: D007093:Imidazoles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; C574806:ETP-46321; C556838:imidazo(1,2-a)pyrazine
keywords: Cancer treatment; Conformational restriction; ETP-46321; PI3K inhibitors