title: Identification and optimisation of a 4',5-bisthiazole series of selective phosphatidylinositol-3 kinase alpha inhibitors.
abstract: Exploring the affinity-pocket binding moiety of a 2-aminothiazole (S)-proline-amide-urea series of selective PI3Kα inhibitors using a parallel-synthesis approach led to the identification of a novel 4',5-bisthiazole sub-series. The synthesis and optimisation of both the affinity pocket and (S)-proline amide moieties within this 4',5-bisthiazole sub-series are described. From this work a number of analogues, including 14 (A66) and 24, were identified as potent and selective PI3Kα inhibitor in vitro tool compounds.
authors.affiliation: Novartis Institutes for BioMedical Research, Global Discovery Chemistry, Novartis Pharma AG, Werk Klybeck, Postfach, CH-4002 Basel, Basel, Switzerland. Electronic address: robin.fairhurst@novartis.com.
authors.forename: Robin A
authors.initials: RA
authors.lastname: Fairhurst
authors.affiliation: Novartis Institutes for BioMedical Research, Global Discovery Chemistry, Novartis Pharma AG, Werk Klybeck, Postfach, CH-4002 Basel, Basel, Switzerland.
authors.forename: Patricia
authors.initials: P
authors.lastname: Imbach-Weese
authors.affiliation: Novartis Institutes for BioMedical Research, Global Discovery Chemistry, Novartis Pharma AG, Werk Klybeck, Postfach, CH-4002 Basel, Basel, Switzerland.
authors.forename: Marc
authors.initials: M
authors.lastname: Gerspacher
authors.affiliation: Novartis Institutes for BioMedical Research, Global Discovery Chemistry, Novartis Pharma AG, Werk Klybeck, Postfach, CH-4002 Basel, Basel, Switzerland.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Caravatti
authors.affiliation: Novartis Institutes for BioMedical Research, Global Discovery Chemistry, Novartis Pharma AG, Werk Klybeck, Postfach, CH-4002 Basel, Basel, Switzerland.
authors.forename: Pascal
authors.initials: P
authors.lastname: Furet
authors.affiliation: Novartis Institutes for BioMedical Research, Global Discovery Chemistry, Novartis Pharma AG, Werk Klybeck, Postfach, CH-4002 Basel, Basel, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Zoller
authors.affiliation: Novartis Institutes for BioMedical Research, Global Discovery Chemistry, Novartis Pharma AG, Werk Klybeck, Postfach, CH-4002 Basel, Basel, Switzerland.
authors.forename: Christine
authors.initials: C
authors.lastname: Fritsch
authors.affiliation: Novartis Institutes for BioMedical Research, Global Discovery Chemistry, Novartis Pharma AG, Werk Klybeck, Postfach, CH-4002 Basel, Basel, Switzerland.
authors.forename: Dorothea
authors.initials: D
authors.lastname: Haasen
authors.affiliation: Novartis Institutes for BioMedical Research, Global Discovery Chemistry, Novartis Pharma AG, Werk Klybeck, Postfach, CH-4002 Basel, Basel, Switzerland.
authors.forename: Joerg
authors.initials: J
authors.lastname: Trappe
authors.affiliation: Novartis Institutes for BioMedical Research, Global Discovery Chemistry, Novartis Pharma AG, Werk Klybeck, Postfach, CH-4002 Basel, Basel, Switzerland.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Guthy
authors.affiliation: Novartis Institutes for BioMedical Research, Global Discovery Chemistry, Novartis Pharma AG, Werk Klybeck, Postfach, CH-4002 Basel, Basel, Switzerland.
authors.forename: Dorothee
authors.initials: D
authors.lastname: Arz
authors.affiliation: Novartis Institutes for BioMedical Research, Global Discovery Chemistry, Novartis Pharma AG, Werk Klybeck, Postfach, CH-4002 Basel, Basel, Switzerland.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Wirth
mesh_terms: D000818:Animals; D058534:Class I Phosphatidylinositol 3-Kinases; D006801:Humans; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry / Q000378:metabolism; D010716:Phosphatidylinositols; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D013844:Thiazoles / Q000737:chemistry* / Q000494:pharmacology*; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology*
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D019869:Phosphatidylinositol 3-Kinases; D010716:Phosphatidylinositols; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D013844:Thiazoles; D014508:Urea; C004483:2-aminothiazole; C484760:PIK3CA protein, human
keywords: Kinase inhibitor; Oncology; Phosphatidylinositol-3-kinase-alpha