title: Preparation and optimization of new 4-(2-(indolin-1-yl)-2-oxoethyl)-2-morpholinothiazole-5-carboxylic acid and amide derivatives as potent and selective PI3Kβ inhibitors.
abstract: In our continuous efforts to identify and develop novel targeted cancer treatments, a new morpholino-thiazole scaffold active against PI3Kβ has been identified. This Letter reports the optimization of this compound class to develop PI3Kβ isoform-selective inhibitors with suitable pharmacological properties.
authors.affiliation: Medicinal Chemistry Oncology Drug Discovery, Sanofi, 13, Quai Jules Guesde, 94400 Vitry-sur-Seine, France. Electronic address: victor.certal@sanofi.com.
authors.forename: Victor
authors.initials: V
authors.lastname: Certal
authors.affiliation: Medicinal Chemistry Oncology Drug Discovery, Sanofi, 13, Quai Jules Guesde, 94400 Vitry-sur-Seine, France.
authors.forename: Frank
authors.initials: F
authors.lastname: Halley
authors.affiliation: Biology Oncology Drug Discovery, Sanofi, 13, Quai Jules Guesde, 94400 Vitry-sur-Seine, France.
authors.forename: Angela
authors.initials: A
authors.lastname: Virone-Oddos
authors.affiliation: Medicinal Chemistry Oncology Drug Discovery, Sanofi, 13, Quai Jules Guesde, 94400 Vitry-sur-Seine, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Filoche-Rommé
authors.affiliation: Medicinal Chemistry Oncology Drug Discovery, Sanofi, 13, Quai Jules Guesde, 94400 Vitry-sur-Seine, France.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Carry
authors.affiliation: Medicinal Chemistry Oncology Drug Discovery, Sanofi, 13, Quai Jules Guesde, 94400 Vitry-sur-Seine, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Gruss-Leleu
authors.affiliation: Medicinal Chemistry Oncology Drug Discovery, Sanofi, 13, Quai Jules Guesde, 94400 Vitry-sur-Seine, France.
authors.forename: Luc
authors.initials: L
authors.lastname: Bertin
authors.affiliation: Medicinal Chemistry Oncology Drug Discovery, Sanofi, 13, Quai Jules Guesde, 94400 Vitry-sur-Seine, France.
authors.forename: Houlfa
authors.initials: H
authors.lastname: Guizani
authors.affiliation: Medicinal Chemistry Oncology Drug Discovery, Sanofi, 13, Quai Jules Guesde, 94400 Vitry-sur-Seine, France.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Pilorge
authors.affiliation: Medicinal Chemistry Oncology Drug Discovery, Sanofi, 13, Quai Jules Guesde, 94400 Vitry-sur-Seine, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Richepin
authors.affiliation: Structural Biology and Molecular Modeling, Sanofi, 13, Quai Jules Guesde, 94400 Vitry-sur-Seine, France.
authors.forename: Andreas
authors.initials: A
authors.lastname: Karlsson
authors.affiliation: Biology Oncology Drug Discovery, Sanofi, 13, Quai Jules Guesde, 94400 Vitry-sur-Seine, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Charrier
authors.affiliation: Drug Safety, Sanofi, 13, Quai Jules Guesde, 94400 Vitry-sur-Seine, France.
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Abecassis
authors.affiliation: Biology Oncology Drug Discovery, Sanofi, 13, Quai Jules Guesde, 94400 Vitry-sur-Seine, France.
authors.forename: Loic
authors.initials: L
authors.lastname: Vincent
authors.affiliation: Biology Oncology Drug Discovery, Sanofi, 13, Quai Jules Guesde, 94400 Vitry-sur-Seine, France.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Nicolas
authors.affiliation: Biology Oncology Drug Discovery, Sanofi, 13, Quai Jules Guesde, 94400 Vitry-sur-Seine, France.
authors.forename: Christoph
authors.initials: C
authors.lastname: Lengauer
authors.affiliation: Medicinal Chemistry Oncology Drug Discovery, Sanofi, 13, Quai Jules Guesde, 94400 Vitry-sur-Seine, France.
authors.forename: Carlos
authors.initials: C
authors.lastname: Garcia-Echeverria
authors.affiliation: Medicinal Chemistry Oncology Drug Discovery, Sanofi, 13, Quai Jules Guesde, 94400 Vitry-sur-Seine, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Schio
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry*; D000818:Animals; D001665:Binding Sites; D018938:Caco-2 Cells; D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000737:chemistry*; D008297:Male; D062105:Molecular Docking Simulation; D010539:Permeability / Q000187:drug effects; 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* / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013844:Thiazoles / Q000737:chemistry
chemical_list: D000577:Amides; D002264:Carboxylic Acids; D007211:Indoles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D013844:Thiazoles; C057812:indoline
keywords: PI3Kβ; PTEN; Thiazole; pAKT